Crystalline 5-(dimethylamino)-n-(4-(morpholinomethyl)phenyl)naphthalene-1-sulfonamide di-hydrochloride di-hydrate

Abstract

To provide a novel compound for treating a disease that is treated by inhibiting the p38α MAPK receptor.SOLUTION: The present invention provides crystalline 5-(dimethylamino)-N-(4-(morpholinomethyl)phenyl)naphthalene-1-sulfonamide dihydrochloride dihydrate, methods of preparing the crystalline salt, pharmaceutical compositions containing the crystalline salt, and methods of treatment using the crystalline salt.SELECTED DRAWING: None

Description

Technical Field

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 106,991, filed Oct. 29, 2020, which is hereby incorporated by reference in its entirety under 35 U.S.C. § 119(e).

[0002] The present invention relates to crystalline 5-(dimethylamino)-N-(4-(morpholinomethyl)phenyl)naphthalene-1-sulfonamide dihydrochloride dihydrate, a method for preparing the crystalline salt, a pharmaceutical composition containing the crystalline salt, and a method of treatment using the crystalline salt.

Background Art

[0003] Mitogen-activated protein kinases (MAPKs) are serine / threonine protein kinases that process and regulate cellular properties in response to a wide range of extracellular stimuli. These enzymes phosphorylate the OH group of serine or threonine in proteins and play important roles in the regulation of cell growth, differentiation, survival, and apoptosis. In mammalian cells, several different MAPKs, including p38 MAPK, have been identified.

[0004] p38 MAPK is a class of MAPKs that respond to stress stimuli such as inflammatory cytokines and reactive oxygen species (ROS) and is involved in a wide range of signaling pathways that stimulate different biological functions. For example, p38 MAPK plays an essential role in the regulation of the inflammatory signaling network and the biosynthesis of cytokines, including tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) in immune cells.

[0005] Research has led to the identification and development of p38 MAPK inhibitors for the treatment of inflammatory diseases such as rheumatoid arthritis and asthma, as p38 MAPK contributes to the development of chronic inflammation.

[0006] p38 MAPK consists of four isoforms (α, β, γ, and δ). p38α MAPK is the first identified isoform of p38 MAPK and was initially recognized as a stress-induced kinase that can be activated by lipopolysaccharide (LPS) and inflammatory cytokines. Inhibition of p38 MAPK has been shown to effectively alleviate inflammatory diseases such as rheumatoid arthritis, cardiovascular diseases, and inflammatory pain.

[0007] Many p38 MAPK catalytic inhibitors are ineffective and cause toxicity that may be due to activity against non-inflammatory p38 and loss of p38α-dependent antagonistic responses. For applications in the treatment of inflammatory and oncology diseases, p38α MAPK inhibitors that can selectively block specific p38α MAPK functions and preserve important counter-regulatory and homeostatic functions are desirable.

Summary of the Invention

[0008] According to the present invention, the compound is crystalline 5-(dimethylamino)-N-(4-(morpholinomethyl)phenyl)naphthalene-1-sulfonamide dihydrochloride dihydrate:

Chemical formula

[0009] According to the present invention, the pharmaceutical composition contains the compound (1).

[0010] According to the present invention, a method for treating a disease in a patient comprises administering a therapeutically effective amount of the compound (1) to a patient in need of such treatment, and the disease is cancer.

[0011] According to the present invention, a method for treating a disease in a patient comprises administering a therapeutically effective amount of the compound (1) to a patient in need of such treatment, and the disease is an inflammatory disease.

[0012] According to the present invention, a method for treating a disease in a patient comprises administering a therapeutically effective amount of compound (1) to a patient in need of such treatment, wherein the disease is an autoimmune disease.

[0013] According to the present invention, a method for treating a disease in a patient comprises administering a therapeutically effective amount of compound (1) to a patient in need of such treatment, wherein the disease is an age-related disease.

[0014] According to the present invention, a method for treating a disease in a patient comprises administering a therapeutically effective amount of compound (1) to a patient in need of such treatment, wherein the disease is selected from acute lung injury, acute respiratory distress syndrome (ARDS), and chronic obstructive pulmonary disease (COPD).

[0015] According to the present invention, a method for inhibiting the p38α MAPK receptor comprises contacting the p38α MAPK receptor with compound (1).

[0016] According to the present invention, a method for inhibiting the p38α MAPK receptor in a patient comprises administering to the patient a pharmacologically effective amount of compound (1).

Brief Description of the Drawings

[0017] The drawings described herein are for illustrative purposes only. The drawings are not intended to limit the scope of the present disclosure.

[0018]

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BEST MODE FOR CARRYING OUT THE INVENTION

[0019] For the purposes of the following detailed description, it is to be understood that the embodiments provided by this disclosure can assume various alternative variations and process sequences unless explicitly specified to the contrary. Further, except where otherwise indicated, e.g., as used in the specification and claims, all numbers expressing amounts of components are to be understood as being modified in all instances by the term "about". Accordingly, unless indicated to the contrary, the numerical parameters set forth in the following specification and attached claims are approximations that can vary depending upon the desired properties sought to be obtained by the present invention. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the claims, each numerical parameter should be construed in light of the reported number of significant digits and by applying ordinary rounding techniques.

[0020] Although the numerical ranges and parameters setting forth the broad scope of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as possible. Nevertheless, each numerical value inherently contains certain errors necessarily resulting from the standard deviation found in their respective test measurements.

[0021] Also, it is to be understood that any numerical range recited herein is intended to include all sub-ranges subsumed therein. For example, a range of "1 to 10" is intended to include all sub-ranges between (and including) the recited minimum value of 1 and the recited maximum value of 10, i.e., having a minimum value of 1 or more and a maximum value of 10 or less.

[0022] The "compounds" and moieties disclosed herein include any particular compound within the disclosed formulas. Compounds can be identified by either chemical structure and / or chemical name. Compounds are named using the ChemDraw Professional 17.1.0.105(19) (PerkinElmer Informatics, Inc.) naming program. If the chemical structure and chemical name conflict, the chemical structure determines the identity of the compound. The compounds described herein may contain one or more stereogenic centers and / or double bonds and thus can exist as stereoisomers such as double bond isomers (i.e., geometric isomers), enantiomers, diastereomers, or atropisomers. Accordingly, any chemical structure shown, in whole or in part, within the scope of this specification in relative configuration encompasses all possible enantiomers and stereoisomers of the shown compound, in stereoisomerically pure form (e.g., geometrically pure, enantiomerically pure, or diastereomerically pure) as well as enantiomeric and stereoisomeric mixtures. Enantiomeric and stereoisomeric mixtures can be resolved into their component enantiomers or stereoisomers using separation techniques or chiral synthesis techniques well known to those skilled in the art.

[0023] The compounds and moieties disclosed herein include the optical isomers of the compounds and moieties, their racemates, and other mixtures thereof. In such embodiments, a single enantiomer or diastereomer can be obtained by asymmetric synthesis or by resolution of a racemate. Resolution of a racemate can be accomplished by conventional methods such as crystallization in the presence of a resolving agent or chromatography using, for example, a chiral high-pressure liquid chromatography (HPLC) column having a chiral stationary phase. In addition, compounds include the (Z)- and (E)-forms (or cis- and trans-forms) of compounds having double bonds, either as a single geometric isomer or a mixture thereof.

[0024] Compounds and moieties may also exist in several tautomeric forms including enol forms, keto forms, and mixtures thereof. Accordingly, the chemical structures shown herein encompass all possible tautomeric forms of the compounds shown. Compounds may exist in solvated forms including non-solvated forms and hydrate forms. Particular compounds may exist in multiple crystalline, co-crystalline, or amorphous forms. Compounds include their pharmaceutically acceptable salts, or pharmaceutically acceptable solvates of any of the foregoing free acid forms, and any of the foregoing crystalline forms.

[0025] Crystalline 5-(dimethylamino)-N-(4-(morpholinomethyl)phenyl)naphthalene-1-sulfonamide dihydrochloride dihydrate is also referred to herein, for convenience, as "crystalline dihydrochloride dihydrate" or "crystalline salt".

[0026] "Immediate release" refers to a pharmaceutical composition that releases substantially all of the pharmaceutically active ingredient into the patient's gastrointestinal tract within less than 1 hour after oral administration, such as within less than 50 minutes, less than 40 minutes, less than 30 minutes, less than 20 minutes, or less than 10 minutes after oral administration. For example, an immediate release dosage form can release more than 90%, more than 95%, or more than 98% of the pharmaceutically active ingredient in the pharmaceutical composition into the gastrointestinal tract within less than 1 hour, such as within less than 50 minutes, less than 40 minutes, less than 30 minutes, less than 20 minutes, or less than 10 minutes after oral administration. An immediate release pharmaceutical composition may be suitable for administering a pharmaceutically active ingredient that is absorbed from the upper part of the gastrointestinal tract into the systemic circulation.

[0027] Examples of "release control" pharmaceutical compositions include controlled release formulations, delayed release formulations, extended release formulations, sustained release formulations, timed release formulations, pulsatile release formulations, and pH-dependent release formulations. These formulations are intended to release the pharmaceutically active ingredient from the pharmaceutical composition after oral administration by the patient and / or at a specific location within the gastrointestinal tract or at a specific pH within the gastrointestinal tract at a desired rate and / or at a desired time. The USP defines a release control system as one selected to achieve a therapeutic efficacy or convenience objective where the time course or location of drug release or both are not achieved by an immediate release dosage form. Release control oral dosage forms can include sustained release and delayed release components. Delayed release dosage forms do not release all of the drug at once, but rather not promptly after administration. Examples of release control formulations include delayed release using an enteric coating, site-specific or time-limited release such as for colon delivery, e.g., sustained release including formulations that can provide a zero-order, first-order, or biphasic release profile, and programmed release such as pulsatile release and delayed sustained release.

[0028] "Extended release" pharmaceutical compositions and coatings provide a long-term dissolution rate after oral administration. Granulation containing granules having an extended release coating may be referred to as extended release granulation. A pharmaceutical composition containing extended release granules may be referred to as an extended release pharmaceutical composition.

[0029] "pH release" pharmaceutical compositions and coatings provide an increased dissolution rate at the intended pH.

[0030] "Pulsatile release" pharmaceutical compositions and coatings exhibit an increased dissolution rate at intervals where the release interval can be determined by time, exposure to an internal stimulus, or exposure to an external stimulus. Examples of pulsatile release systems include capsule systems, osmotic pressure systems, systems having an erodible membrane, and systems having a rupturable coating. Examples of stimuli include temperature, chemicals, electrical stimulation, and magnetic stimulation.

[0031] "Timed-release" pharmaceutical compositions and coatings have a dissolution rate that is a function of time. Timed-release pharmaceutical compositions or coatings include, for example, delayed-release, sustained release, and extended-release pharmaceutical compositions and coatings.

[0032] "Delayed-release" pharmaceutical compositions and coatings result in an increased dissolution rate at an intended time after administration.

[0033] "Modulate" and "modulation" refer to, for example, a change in the biological activity of a biological molecule such as a protein, gene, peptide, or antibody, and such a change can be related to an increase in biological activity such as increased activity, agonism, activation, expression, upregulation, and / or increased expression, or a decrease in biological activity such as decreased activity, antagonism, inhibition, deactivation, downregulation, and / or decreased expression for the biological molecule. For example, Compound (2) can modulate the p38α MAPK protein, such as by inhibiting the p38α MAPK protein. Compound (2) can selectively modulate, such as by selectively inhibiting the p38α MAPK protein compared to other MAPK or p38 MAPK proteins. Compound (2) can selectively modulate, such as by selectively inhibiting the p38α MAPK protein compared to other MAPK or p38 MAPK proteins.

[0034] "Moiety" refers to a particular segment or functional group of a molecule. A chemical moiety is often recognized as a chemical entity that is embedded within or attached to a molecule.

[0035] "Patient" refers to a mammal, for example, a human.

[0036] "Pharmaceutically acceptable" refers to those approved or approvable by a regulatory agency of the Federal or State government or listed in the United States Pharmacopeia or other generally recognized pharmacopeias for use in animals and more particularly in humans.

[0037] "Pharmaceutically acceptable vehicle" refers to a pharmaceutically acceptable diluent, adjuvant, excipient, carrier, or any combination of the foregoing, with which a compound provided by the present disclosure can be administered to a patient, which does not destroy its pharmacological activity and is non-toxic when administered in a dosage sufficient to provide a therapeutically effective amount of the compound.

[0038] "Pharmaceutical composition" refers to a compound (1) and at least one pharmaceutically acceptable vehicle with which the compound (1) is administered to a patient. Pharmaceutically acceptable vehicles are known in the art.

[0039] "Disease" refers to any of the foregoing diseases, disorders, conditions or symptoms.

[0040] "Preventing" or "prevention" refers to reducing the risk of contracting a disease or disorder (i.e., not causing at least one of the clinical symptoms of a disease in a patient who may be exposed to the disease or is susceptible to the disease but has not yet experienced or manifested the symptoms of the disease). In some embodiments, "preventing" or "prevention" refers to reducing the symptoms of a disease by prophylactically administering a compound provided by the present disclosure. The application of a therapeutic agent for preventing a disease or disorder or for its prevention is known as "prophylaxis". The compounds provided by the present disclosure can provide excellent prophylaxis due to lower long-term side effects over a long period of time.

[0041] "Curing" a disease refers to eliminating the disease or disorder or eliminating the symptoms of the disease or disorder.

[0042] "Treating" or "treatment" of a disease or disorder refers to inhibiting, preventing, alleviating, causing regression of, reducing the severity of, delaying the onset of, alleviating, and / or stabilizing a disease or disorder, or one or more clinical symptoms of a disease or disorder. "Treating" or "treatment" of a disease or disorder includes producing a clinically beneficial effect without curing the underlying disease or disorder.

[0043] "Therapeutically effective amount" refers to an amount of a compound, such as a pharmaceutically active ingredient, that is sufficient to have an effect on the treatment of a disease or at least one of the clinical symptoms of a disease when administered to a patient. A "therapeutically effective amount" can vary, for example, according to the compound, the disease and / or symptoms of the disease, the severity of the disease and / or symptoms of the disease or disorder, the age, weight, and / or health status of the patient to be treated, and the judgment of the prescribing physician. A therapeutically effective amount in any given case can be ascertained by one of ordinary skill in the art or determined by routine experimentation.

[0044] "Therapeutically effective dose" refers to a dose that provides effective treatment of a disease or disorder in a patient. A therapeutically effective dose can vary depending on the compound and on the patient and can depend on factors such as the condition of the patient and the route of delivery. A therapeutically effective dose can be determined according to routine pharmacological procedures known to those of ordinary skill in the art.

[0045] "Vehicle" refers to a diluent, excipient, or carrier administered to a patient together with a compound. A vehicle can be a pharmaceutically acceptable vehicle. Pharmaceutically acceptable vehicles are known in the art.

[0046] Here, crystalline 5-(dimethylamino)-N-(4-(morpholinomethyl)phenyl)naphthalene-1-sulfonamide dihydrochloride dihydrate, a method for preparing the crystalline salt, a pharmaceutical composition containing the crystalline salt, and the crystalline salt are mentioned. The disclosed crystalline salt, pharmaceutical composition, method, and use are not intended to limit the scope of the claims. On the contrary, the scope of the claims is intended to include all alternatives, modifications, and equivalents.

[0047] Compound (1), crystalline 5-(dimethylamino)-N-(4-(morpholinomethyl)phenyl)naphthalene-1-sulfonamide dihydrochloride dihydrate, is a stable salt of 5-(dimethylamino)-N-(4-(morpholinomethyl)phenyl)naphthalene-1-sulfonamide, Compound (2). Compound (1) has the following structure. [Chemical formula]

[0048] 5-(Dimethylamino)-N-(4-(morpholinomethyl)phenyl)naphthalene-1-sulfonamide is a substrate-selective p38α MAPK inhibitor. 5-(Dimethylamino)-N-(4-(morpholinomethyl)phenyl)naphthalene-1-sulfonamide (free base, Compound 2) has the structure of formula (2). [Chemical formula]

[0049] The synthesis method of Compound (2) and the properties of Compound (2) are disclosed in PCT International Publication No. WO2020 / 118194.

[0050] Compound (1), crystalline 5-(dimethylamino)-N-(4-(morpholinomethyl)phenyl)naphthalene-1-sulfonamide dihydrochloride dihydrate, is a stable salt of the free base compound (2).

[0051] The crystalline 5-(dimethylamino)-N-(4-(morpholinomethyl)phenyl)naphthalene-1-sulfonamide dihydrochloride dihydrate salt can be prepared as described in Example 1.

[0052] Compound (1) can be characterized by an XRPD pattern that includes diffraction peaks characteristic of at least 10.5° ± 0.2°, 13.9° ± 0.2°, 14.8° ± 0.2°, 17.2 ± 0.2°, 20.4 ± 0.2°, 22.6 ± 0.2°, 25.7 ± 0.2°, and 27.9 ± 0.2°, expressed as 2θ angles and determined using Cu-Kα radiation.

[0053] Compound (1) can be characterized by an XRPD pattern that includes diffraction peaks characteristic of at least 10.5° ± 0.1°, 13.9° ± 0.1°, 14.8° ± 0.1°, 17.2 ± 0.1°, 20.4 ± 0.1°, 22.6 ± 0.1°, 25.7 ± 0.1°, and 27.9 ± 0.2°, expressed as 2θ angles and determined using Cu-Kα radiation.

[0054] Compound (1) can be characterized by an XRPD pattern that includes diffraction peaks characteristic of at least 7.5 ± 0.2°, 8.5 ± 0.2°, 10.5° ± 0.2°, 12.8 ± 0.2°, 13.9° ± 0.2°, 14.8° ± 0.2°, 15.5 ± 0.2°, 17.2 ± 0.2°, 18.2 ± 0.2°, 20.1 ± 0.2°, 20.4 ± 0.2°, 21.1 ± 0.2°, 22.6 ± 0.2°, 22.9 ± 0.2°, 23.5 ± 0.2°, 23.8 ± 0.2°, 24.6 ± 0.2°, 25.7 ± 0.2°, 26.1 ± 0.2°, 26.4 ± 0.2°, 27.1 ± 0.2°, 27.5 ± 0.2°, 27.9 ± 0.2°, and 32.4 ± 0.2°, expressed as 2θ angles and determined using Cu-Kα radiation.

[0055] Compound (1) can be characterized by an XRPD pattern that exhibits diffraction peaks at least at 2θ angles of 7.5±0.1°, 8.5±0.1°, 10.5°±0.1°, 12.8±0.1°, 13.9°±0.1°, 14.8°±0.1°, 15.5±0.1°, 17.2±0.1°, 18.2±0.1°, 20.1±0.1°, 20.4±0.1°, 21.1±0.1°, 22.6±0.1°, 22.9±0.1°, 23.5±0.1°, 23.8±0.1°, 24.6±0.1°, 25.7±0.1°, 26.1±0.1°, 26.4±0.1°, 27.1±0.1°, 27.5±0.1°, 27.9±0.1°, and 32.4±0.1°, determined using Cu-Kα radiation.

[0056] Compound (1) can be characterized by an XRPD pattern substantially as shown in Figure 1.

[0057] Compound (1) can have a melting onset temperature in the range of 161°C to 167°C, such as 162°C to 166°C, or 163°C to 165°C, and the melting onset temperature is determined by differential scanning calorimetry.

[0058] Compound (1) can have a melting onset temperature of 164.3°C±0.5°C, such as 164.3°C±0.25°C, or 164.3°C±0.1°C, and the melting onset temperature is determined by differential scanning calorimetry.

[0059] Compound (1) can have a melting enthalpy in the range of 89 J / g to 99 J / g, 91 J / g to 97 J / g, or 93 J / g to 95 J / g, and the melting enthalpy is determined by differential scanning calorimetry.

[0060] Compound (1) can have a melting enthalpy of 94.2 J / g±0.5 J / g, such as 94.2 J / g±0.25 J / g, or 94.2 J / g±0.1 J / g, and the melting enthalpy is determined by differential scanning calorimetry.

[0061] Compound (1) can have a melting peak, for example, in the range of 178.5 J / g to 184.5 J / g, 179.5 J / g to 183.5 J / g, or 179.5 J / g to 182.5 J / g, and the melting peak is determined by differential scanning calorimetry.

[0062] Compound (1) can have a melting peak at 181.6 °C ± 2.0 °C, such as 181.6 °C ± 1.0 °C, or 181.6 °C ± 0.5 °C, and the melting peak is determined by differential scanning calorimetry.

[0063] Compound (1) can exhibit a differential scanning calorimetry curve, substantially as shown in Figure 2.

[0064] Compound (1) can have a weight loss of 13% to 15% at a temperature of 25 °C to 210 °C, for example, 13.3% to 14.7% or 13.6% to 14.4% at a temperature of 25 °C to 210 °C, and the weight loss is determined by thermogravimetric analysis at a scanning rate of 2 °C / min.

[0065] Compound (1) can have a weight loss of 13.9% ± 1.0%, such as 13.9% ± 0.5% or 13.9% ± 0.2%, at a temperature of 25 °C to 210 °C, and the weight loss is determined by thermogravimetric analysis at a scanning rate of 2 °C / min.

[0066] Compound (1) provided by the present disclosure can exhibit a differential calorimetry curve substantially as shown in Figure 3.

[0067] Compound (1) can have a weight loss of 2% to 6% at a temperature of 25 °C to 122 °C, for example, 3% to 5% or 3.75% to 4.75% at a temperature of 25 °C to 122 °C, and the weight loss is determined by thermogravimetric analysis at a scanning rate of 4.25 °C / min.

[0068] Compound (1) can have a weight loss of 4.25% ± 1.0%, such as 4.25% ± 0.5% or 4.25% ± 0.2%, at a temperature of 25 °C to 122 °C, and the weight loss is determined by thermogravimetric analysis at a scanning rate of 4.25 °C / min.

[0069] Compound (1) provided by the present disclosure can substantially exhibit a differential calorimetry curve as shown in Figure 4.

[0070] Compound (1) can have a water content of 5.8 mol% to 6.6 mol%, such as 5.9 mol% to 6.5 mol%, 6.0 mol% to 6.4 mol%, 6.1 mol% to 6.3 wt%, or 6.2 mol%, and mol% is based on the total moles of compound (1).

[0071] 5-(Dimethylamino)-N-(4-(morpholinomethyl)phenyl)naphthalene-1-sulfonamide, free base, can be prepared as described in PCT International Publication No. WO2020 / 118194.

[0072] The XRPD pattern of the crystalline anhydrous compound (2) is shown in Figure 5.

[0073] Compound (2) can be characterized by an XRPD pattern that includes diffraction peaks characteristic of at least 13.1° ± 0.2°, 14.6° ± 0.2°, 15.0° ± 0.2°, 18.1 ± 0.2°, 22.2 ± 0.2°, 22.6 ± 0.2°, and 24.4 ± 0.2°, expressed as 2θ angles and determined using Cu-Kα radiation.

[0074] Compound (2) can be characterized by an XRPD pattern that includes diffraction peaks characteristic of at least 13.1° ± 0.1°, 14.6° ± 0.1°, 15.0° ± 0.1°, 18.1 ± 0.1°, 22.2 ± 0.1°, 22.6 ± 0.1°, and 24.4 ± 0.1°, expressed as 2θ angles and determined using Cu-Kα radiation.

[0075] Compound (2) can have a primary melting onset temperature of, for example, 158 °C to 164 °C, such as 159 °C to 163 °C, or 160 °C to 162 °C, and the melting onset temperature is determined by differential scanning calorimetry.

[0076] Compound (2) can have a primary melting onset temperature of, for example, 160.9 °C ± 0.5 °C, such as 160.9 °C ± 0.25 °C, or 160.9 °C ± 0.1 °C, and the melting onset temperature is determined by differential scanning calorimetry.

[0077] Compound (2) can have a primary melting enthalpy of, for example, 60 J / g to 65 J / g, 61 J / g to 65 J / g, or 62 J / g to 4 J / g, and the melting enthalpy is determined by differential scanning calorimetry.

[0078] Compound (2) can have a primary melting enthalpy of, for example, 62.8 J / g ± 0.5 J / g, such as 62.8 J / g ± 0.25 J / g, or 62.8 J / g ± 0.1 J / g, and the melting enthalpy is determined by differential scanning calorimetry.

[0079] Compound (2) can have a primary melting peak of, for example, 175 J / g to 182 J / g, 176 J / g to 181 J / g, or 177 J / g to 180 J / g, and the melting peak is determined by differential scanning calorimetry.

[0080] Compound (2) can have a primary melting peak at, for example, 177.8 °C ± 2.0 °C, such as 177.8 °C ± 1.0 °C, or 177.8 °C ± 0.5 °C, and the melting peak is determined by differential scanning calorimetry.

[0081] Compound (2) can have a secondary melting onset temperature of 204.7 °C, a secondary melting enthalpy of 20.7 J / g, and a secondary melting peak of 211.2 °C.

[0082] Compound (2) can exhibit a differential scanning calorimetry curve, substantially as shown in Figure 6.

[0083] The crystalline 5-(dimethylamino)-N-(4-(morpholinomethyl)phenyl)naphthalene-1-sulfonamide dihydrochloride monohydrate (Compound (3)) can be produced by exposing the crystalline 5-(dimethylamino)-N-(4-(morpholinomethyl)phenyl)naphthalene-1-sulfonamide dihydrochloride to moisture. The dihydrochloride monohydrate can have a water content of 3.9 mol%.

[0084] The XRPD pattern of 5-(dimethylamino)-N-(4-(morpholinomethyl)phenyl)naphthalene-1-sulfonamide dihydrochloride monohydrate is shown in Figure 7.

[0085] The dihydrochloride monohydrate can be characterized by an XRPD pattern that is represented as 2θ angles and includes diffraction peaks characteristic of at least 13.1° ± 0.2°, 14.7° ± 0.2°, 18.1° ± 0.2°, 22.2 ± 0.2°, 22.6 ± 0.2°, 24.5 ± 0.2°, and 25.7 ± 0.2°, which were determined using Cu-Kα radiation.

[0086] The dihydrochloride monohydrate can be characterized by an XRPD pattern that is represented as 2θ angles and includes diffraction peaks characteristic of at least 13.1° ± 0.1°, 14.7° ± 0.1°, 18.1° ± 0.1°, 22.2 ± 0.1°, 22.6 ± 0.1°, 24.5 ± 0.1°, and 25.7 ± 0.1°, which were determined using Cu-Kα radiation.

[0087] The dihydrochloride monohydrate can have a melting onset temperature of 159°C to 166°C, such as 160°C to 165°C, or 161°C to 164°C, and the melting onset temperature is determined by differential scanning calorimetry.

[0088] The dihydrochloride monohydrate can have a melting onset temperature of 162.9°C ± 0.5°C, such as 162.9°C ± 0.25°C, or 162.9°C ± 0.1°C, and the melting onset temperature is determined by differential scanning calorimetry.

[0089] The dihydrochloride monohydrate can have a melting enthalpy of, for example, 92 J / g to 98 J / g, 93 J / g to 97 J / g, or 94 J / g to 96 J / g over a temperature range of 163°C to 194°C, and the melting enthalpy is determined by differential scanning calorimetry.

[0090] The dihydrochloride monohydrate can have a melting enthalpy of 94.9 J / g ± 0.5 J / g, such as 94.9 J / g ± 0.25 J / g, or 94.9 J / g ± 0.1 J / g, over a temperature range of 163°C to 194°C, and the melting enthalpy is determined by differential scanning calorimetry.

[0091] The dihydrochloride monohydrate can have a melting peak of, for example, 175 J / g to 182 J / g, 176 J / g to 181 J / g, or 177 J / g to 180 J / g, and the melting peak is determined by differential scanning calorimetry.

[0092] The dihydrochloride monohydrate can have a primary melting peak at 178.0°C ± 2.0°C, such as 178.0°C ± 1.0°C, or 178.0°C ± 0.5°C, and the melting peak is determined by differential scanning calorimetry.

[0093] The dihydrochloride monohydrate salt can exhibit a differential scanning calorimetry curve, substantially as shown in Figure 8.

[0094] Compound (1) can be synthesized using methods known in the art.

[0095] Compound (1) can be prepared according to Scheme 5, as disclosed in paragraph

[0277] of PCT International Publication No. PCT / US2019 / 064960 or as described in Example 1.

[0096] To prepare the dihydrochloride, 5-(dimethylamino)-N-(4-(morpholinomethyl)phenyl)naphthalene-1-sulfonamide (free base) is reacted with hydrogen chloride in an organic solvent in methanol to obtain 5-(dimethylamino)-N-(4-(morpholinomethyl)phenyl)naphthalene-1-sulfonamide dihydrochloride. To provide the dihydrochloride dihydrate salt, the dihydrochloride can be suspended in methanol (3.0 volumes) and water (2.0 equivalents) and stirred at 25 °C to 30 °C for 1 hour. The solid can be filtered and washed with methanol (1.5 volumes) to provide the compound (1) with a water content of 6.2 mol%.

[0097] The pharmaceutical composition provided by the present disclosure can contain compound (1).

[0098] The pharmaceutical composition can contain a therapeutically effective amount of compound (1) for treating a disease in a patient.

[0099] The pharmaceutical composition can contain one or more pharmaceutically acceptable carriers, excipients, diluents, or any combination of the foregoing.

[0100] Compound (1) can be incorporated into a pharmaceutical composition to be administered to a patient by any suitable route of administration including intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, oral, peroral, sublingual, intracerebral, intravaginal, transdermal, rectal, inhalation, or topical. The pharmaceutical composition provided by the present disclosure can be an injectable formulation. The pharmaceutical composition provided by the present disclosure can be an injectable intravenous formulation. The pharmaceutical composition provided by the present disclosure can be an oral formulation. The oral formulation can be an oral dosage form. The pharmaceutical composition can be formulated for intravenous administration or subcutaneous administration.

[0101] The pharmaceutical composition provided by the present disclosure may include a therapeutically effective amount of compound (1) together with a suitable amount of one or more pharmaceutically acceptable vehicles to provide a composition for appropriate administration to a patient. Suitable pharmaceutical vehicles and methods of preparing pharmaceutical compositions are described in the art.

[0102] After administration to a patient, compound (1) dissociates to provide the parent compound, 5-(dimethylamino)-N-(4-(morpholinomethyl)phenyl)naphthalene-1-sulfonamide, compound (2).

[0103] The pharmaceutical composition provided by the present disclosure can be formulated for oral administration. The pharmaceutical composition formulated for oral administration can include any suitable oral dosage form, such as tablets, capsules, caplets, sachets, bottles, stick packs, dispersions, and suspensions.

[0104] The pharmaceutical composition formulated for oral administration can provide a release modulation profile in the gastrointestinal tract, such as a controlled release profile, a sustained release profile, a pH release profile, a pulsatile release profile, a timed-release profile, or a delayed release profile. The pharmaceutical composition formulated for oral administration can be configured to release compound (1) over an intended period after ingestion and / or in an intended region of the gastrointestinal tract.

[0105] The pharmaceutical composition formulated for oral administration can provide an immediate release profile.

[0106] Evaluating the response of a single patient to treatment and identifying the optimal treatment for the patient is one of the greatest challenges in modern medicine and is related to the trend of personalized medicine. Compound (1) can have target selectivity, for example, for certain cancers and immune cells. Using a radioactively labeled Compound (1) for positron emission tomography (PET) or single photon emission computed tomography (SPECT), it is possible to predict the targeting of treatment based on single-case-by-case patient analysis, thus excluding patients who are expected not to benefit from the treatment. A PET / SPECT scan using Compound (1) can provide a three-dimensional distribution map when correlated with concentration, which can then be used for macroscopic dosimetry calculations.

[0107] Therefore, assaying and using Compound (1) and / or its pharmaceutical composition for therapy is within the ability of those skilled in the art.

[0108] Compound (1) and / or its pharmaceutical composition can generally be used in an effective amount to achieve the intended purpose. For use in treating diseases such as cancer, autoimmune diseases, or inflammatory diseases, Compound (1) can be administered or applied in a therapeutically effective amount.

[0109] The amount of Compound (1) that would be effective in treating a particular disorder or condition disclosed herein depends in part on the nature of the disease or condition and can be determined by standard clinical techniques known in the art. In addition, in vitro or in vivo assays can optionally be used to help identify the optimal dosage range. The amount of Compound (1) will depend on, among other factors, the patient being treated, the patient's weight, the severity of the affliction, the mode of administration, and the judgment of the prescribing physician.

[0110] Compound (1) can be assayed in vitro and in vivo for the desired therapeutic activity before use in humans. For example, in vitro assays can be used to determine whether administration of a particular compound or combination of compounds is preferred. Compounds can also be demonstrated to be effective and safe using animal model systems.

[0111] A therapeutically effective dose of compound (1) and / or its pharmaceutical composition will provide a therapeutic benefit without causing substantial toxicity. The toxicity of compound (1) and / or its pharmaceutical composition can be determined using standard pharmaceutical procedures and can be readily confirmed by those skilled in the art. The dose ratio between the toxic effect and the therapeutic effect is the therapeutic index. Compound (1) and / or its pharmaceutical composition exhibit a particularly high therapeutic index in treating diseases and disorders. The dose of compound (1), and / or its pharmaceutical composition can be within the range of circulating concentrations that include an effective dose with minimal toxicity.

[0112] Compound (1) or its pharmaceutical composition can be included in a kit that can be used to administer the compound to a patient for therapeutic purposes. The kit can include a pharmaceutical composition containing compound (1) suitable for administration to a patient and instructions for use for administering the pharmaceutical composition to the patient. The kit can be suitable for treating cancer, treating autoimmune diseases, or treating inflammatory diseases. The kit can include compound (1), a pharmaceutically acceptable vehicle for administering the cocrystal, and instructions for use for administering the formulation containing the cocrystal to a patient.

[0113] The pharmaceutical composition can be included in a container, pack, or dispenser together with instructions for use for administration.

[0114] The instructions for use supplied with the kit can be printed and / or supplied, for example, as an electronically readable medium, a video cassette, an audio tape, a flash memory device, or can be published on an Internet website, or can be distributed to the patient and / or healthcare provider as an electronic communication.

[0115] Compound (1) and a pharmaceutical composition containing compound (1) can be used for treating a disease in which the etiology of the disease is associated with p38α MAPK protein activity.

[0116] Compound (1) dissociates in vivo to give compound (2), which is a selective inhibitor of p38α MAPK. The selective p38α MAPK inhibitor has a higher binding affinity for the catalytic binding site of p38α MAPK than for the target pocket of p38α MAPK. The p38α MAPK inhibitor can bind to p38α MAPK near the substrate binding groove of p38α MAPK, which extends between the CD and ED domains and two acidic regions. The binding pocket can be defined by at least the residues R49, H107, L108, and K165 of p38α MAPK. The binding pocket can be defined by at least the residues R49, H107, L108, M109, G110, A157, V158, E163, L164, and K165 of p38α MAPK.

[0117] The selective binding of compound (2) to p38α MAPK can be confirmed using complementary techniques. For example, the selective p38α MAPK inhibitor can show a concentration-dependent increase in the melting temperature of p38α but not p38β, as determined using DSF, which detects ligand-induced protein stabilization. Specific compound binding to p38α can be confirmed and the interaction with its aromatic ring localized using STD-NMR, which measures low-affinity protein / ligand binding via non-scalar magnetization transfer from the protein to the ligand proton. The p38α MAPK inhibitor can cause a concentration-dependent increase in the melting temperature of p38α MAPK. The difference in melting temperature T m can be measured at a p38α MAPK inhibitor concentration of 1 nM to 1000 μM, for example, at a concentration of 100 μM. For example, the difference in melting temperature can be from 0.1 °C to about 2 °C.

[0118] Compound (2) can interact with the pocket near the ED substrate docking site of p38 MAPK.

[0119] Compound (2) can bind to p38α MAPK near the substrate-binding groove of p38α MAPK that extends between the CD and ED domains.

[0120] Compound (2) can inhibit MK2 phosphorylation through its interaction with p38α MAPK.

[0121] Compound (2) can bind to p38α MAPK competitively with 4-chloro-N-(4-((1,1-dioxidothiomorpholino)methyl)phenyl)benzamide.

[0122] Compound (2) has a higher binding affinity for the p38α MAPK subunit than for the p38β MAPK subunit.

[0123] The p38α MAPK inhibitor can have a logP, for example, of -5 to 10, -3 to 8, 0 to 5, 0.1 to 3, 0.1 to 1, 0.5 to 1.5, 0.75 to 2, 1 to 2.5, or 1.75 to 3. LogP is a measure of drug solubility and is defined as the logarithm of the octanol / water partition coefficient of the drug.

[0124] The phosphorylation of MK2 requires binding to the ED site adjacent to the target pocket in p38α MAPK. The target pocket can be defined by the amino acids R49, Hl07, Ll08, and Kl65 in p38α MAPK. The target pocket can be defined by the amino acids selected from R49, Hl07, Ll08, M109, Gl10, Al57, Vl58, El63, Ll64, and Kl65 in p38α MAPK. The target pocket can be defined by the amino acids R49, Hl07, Ll08, M109, Gl10, Al57, Vl58, El63, Ll64, and Kl65 in p38α MAPK.

[0125] Compound (2) can at least partially inhibit MK2 phosphorylation. For example, Western blotting can be used to measure the inhibition of MK2 phosphorylation in anisomycin-stimulated HeLa cells by compound (2).

[0126] Compound (2) can stabilize endothelial or epithelial barrier function. Endothelial barrier permeability can be measured by separate or combined exposure to TNFα and hyperthermia therapy, followed by measurement of permeability for 10 kDa dextran. For example, endothelial barrier stabilization can be evaluated by pretreatment with compound (2), with permeability measurements taken before and after, and stabilization can be expressed as the percentage reduction in increased permeability before and after pretreatment. The increased permeability of 10 kDa dextran can be reduced by, for example, more than 5%, more than 10%, more than 20%, more than 40%, more than 60%, more than 80%, or more than 100%, i.e., a reduction of 5% - 100%.

[0127] Compound (2) can regulate TNFα-induced gene expression in human microvascular endothelial cells of the lung (HMVEC-L), as determined, for example, using RNASeq. For example, HMVEC-L can be pretreated with an appropriate concentration of a p38α MAPK inhibitor for a certain period of time and then stimulated with TNFα for a certain period of time. Compound (1) can inhibit genes such as PRRG4, TSLP, CCL17, EXOC3L4, MMP9, IDO1, CXCL10, CD200, SLC15A3, VDR, IL1B, GPR88, CD207, TCHH, HAS3, GBP1P1, MUC4, ELOVL7, CXCL11, GBP4, PLA2A, and / or CXCL5.

[0128] The effect of a p38α MAPK inhibitor on inflammatory cytokine expression can be determined by pretreating PMA-differentiated THP-1 cells with the p38α MAPK inhibitor, then stimulating with LPS, and subsequently collecting RNA for a certain period of time for analysis by PCR-based cytokine array. The p38α MAPK inhibitor can inhibit the expression of various genes such as IL-1A, IL-8, TNFSF8, CXCL5, CCL7, CCL17, TNFSF9, IL-1B, CXCL1, TNFSF15, CCL5, CCL4, CCL20, CXCL2, TNF, or BMP6. The p38α MAPK inhibitor can drive the differentiation of Foxp3+ regulatory cells and inhibit the expression of Smad3 that suppresses interferon-γ. Reduction of inflammation can be measured by comparing fold change mRNA levels at various concentrations of the p38α MAPK inhibitor to unstimulated PMA-differentiated THP-1 cells.

[0129] Compound (1) or a pharmaceutical composition thereof can be used to treat a disease in a patient.

[0130] Compound (1) or a pharmaceutical composition thereof can be used to treat a disease in which the etiology of the disease is associated with upregulation and / or downregulation of the p38α MAPK protein.

[0131] The method provided by the present disclosure for treating a disease in a patient comprises administering to a patient in need of such treatment a therapeutically effective amount of compound (1) or a pharmaceutical composition thereof, wherein the disease is treated by inhibiting the p38α MAPK protein.

[0132] The p38 mitogen-activated protein kinase (MAPK) family of stress- and cytokine-activated kinases is associated with the etiology of many human diseases, including, for example, cancer, rheumatoid arthritis, cardiovascular disease, multiple sclerosis, inflammatory bowel disease, chronic obstructive pulmonary disease (COPD), asthma, acute respiratory distress syndrome (ARDS), and acute lung injury (ALI). Among the many important biological processes regulated by p38 MAPK, the regulation of endothelial and epithelial barrier function, leukocyte trafficking, and cytokine expression are central to the etiology of acute and chronic inflammatory disorders.

[0133] Compound (1) and its pharmaceutical compositions can be used to treat cancer in a patient. The cancer can be, for example, a solid tumor or a metastasis.

[0134] The methods provided by the present disclosure include methods of treating cancer in a patient, comprising administering to the patient in need of such treatment a therapeutically effective amount of a compound or pharmaceutical composition provided by the present disclosure.

[0135] Examples of suitable cancers include acoustic neuroma, adenocarcinoma, angiosarcoma, astrocytoma, basal cell carcinoma, bile duct carcinoma, bladder cancer, brain cancer, breast cancer, bronchogenic carcinoma, cervical cancer, chordoma, choriocarcinoma, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, embryonal carcinoma, endothelial carcinoma, epithelioma, esophageal cancer, Ewing's tumor, fibrosarcoma, gastric cancer, glioblastoma multiforme, glioma, head and neck cancer, hemangioblastoma, liver cancer, kidney cancer, leiomyosarcoma, liposarcoma, lung cancer, lymphangioendotheliosarcoma, lymphangiosarcoma, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, myosarcoma, nasal cancer, neuroblastoma, oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinoma, papillary carcinoma, pinealoma, prostate cancer, rhabdomyosarcoma, rectal cancer, renal cell carcinoma, retinoblastoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, squamous cell carcinoma, stomach cancer, sweat gland carcinoma, synovioma, testicular cancer, small cell lung cancer, pharyngeal cancer, uterine cancer, Wilms' tumor, blood cancer, acute erythroblastic leukemia, acute lymphoblastic B cell leukemia, acute lymphoblastic T cell leukemia, acute lymphoblastic leukemia, acute megakaryoblastic leukemia, acute monoblastic leukemia, acute myeloblastic leukemia, acute myelomonocytic leukemia, acute non-lymphocytic leukemia, acute promyelocytic leukemia, acute undifferentiated leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, hairy cell leukemia, multiple myeloma, heavy chain disease, Hodgkin's disease.

[0136] Examples of suitable cancers include pancreatic cancer, breast cancer, prostate cancer, lymphoma, skin cancer, colon cancer, melanoma, malignant melanoma, ovarian cancer, brain cancer, primary brain tumor, head and neck cancer, glioma, glioblastoma, liver cancer, bladder cancer, non-small cell lung cancer, head and neck tumor, breast tumor, ovarian tumor, lung tumor, small cell lung tumor, Wilms tumor, cervical tumor, testicular tumor, bladder tumor, pancreatic tumor, stomach tumor, colon tumor, prostate tumor, urogenital tumor, thyroid tumor, esophageal tumor, myeloma, multiple myeloma, adrenal tumor, renal cell tumor, endometrial tumor, adrenocortical tumor, malignant pancreatic insulinoma, malignant carcinoid tumor, choriocarcinoma, fungating polyposis, malignant hypercalcemia, cervical hyperplasia, leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, chronic granulocytic leukemia, acute granulocytic leukemia, hairy cell leukemia, neuroblastoma, rhabdomyosarcoma, Kaposi's sarcoma, polycythemia vera, essential thrombocythemia, Hodgkin's disease, non-Hodgkin's lymphoma, soft tissue sarcoma, osteogenic sarcoma, primary macroglobulinemia, or retinoblastoma, and the like.In other embodiments, the cancer is a schwannoma, adenocarcinoma, angiosarcoma, astrocytoma, basal cell carcinoma, bile duct cancer, bladder cancer, brain cancer, breast cancer, bronchogenic cancer, cervical cancer, chordoma, choriocarcinoma, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, embryonal cancer, endothelial cancer, epithelioma, esophageal cancer, Ewing's tumor, fibrosarcoma, gastric cancer, glioblastoma multiforme, glioma, head and neck cancer, hemangioblastoma, liver cancer, kidney cancer, leiomyosarcoma, liposarcoma, lung cancer, lymphangioendotheliosarcoma, lymphangiosarcoma, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, myosarcoma, nasal cancer, neuroblastoma, oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinoma, papillary carcinoma, pinealoma, prostate cancer, rhabdomyosarcoma, rectal cancer, renal cell carcinoma, retinoblastoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, squamous cell carcinoma, stomach cancer, sweat gland carcinoma, synovioma, testicular cancer, small cell lung cancer, pharyngeal cancer, uterine cancer, Wilms' tumor, blood cancer, acute erythroblastic leukemia, acute lymphoblastic B cell leukemia, acute lymphoblastic T cell leukemia, acute lymphoblastic leukemia, acute megakaryoblastic leukemia, acute monoblastic leukemia, acute myeloblastic leukemia, acute myelomonocytic leukemia, acute non-lymphocytic leukemia, acute promyelocytic leukemia, acute undifferentiated leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, hairy cell leukemia, multiple myeloma, heavy chain disease, Hodgkin's disease, multiple myeloma, non-Hodgkin's lymphoma, polycythemia vera, or Waldenström macroglobulinemia.

[0137] Compound (1) or its pharmaceutical composition is used for, for example, the following cancers: acute lymphoblastic leukemia, acute myeloid leukemia, adrenocortical carcinoma, appendix cancer, astrocytoma, atypical teratoid / rhabdoid tumor, basal cell carcinoma (non-melanoma), B-cell lymphoma, bladder cancer, bone cancer, brain and spinal cord tumors, brainstem cancer, brain tumor, breast cancer, bronchial tumor, Burkitt lymphoma, carcinoid tumor, head and neck cancer, central nervous system fetal tumor, cerebellar astrocytoma, cerebral astrocytoma / malignant glioma, cervical cancer, chordoma, chronic lymphocytic leukemia, chronic myeloid leukemia, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, desmoplastic small round cell tumor, ductal breast cancer, melanoma, endocrine pancreatic tumor (islet cell tumor), endometrial cancer, ependymoblastoma, esophageal cancer, nasal neuroblastoma, Ewing family of tumors, extracranial germ cell tumor, extrahepatic bile duct cancer, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor, gestational trophoblastic tumor, glioblastoma, glioma, hairy cell leukemia, head and neck cancer, heart cancer, hematopoietic tumors of lymphoid lineage, hepatocellular carcinoma, Hodgkin lymphoma, hypopharyngeal cancer, hypothalamic and visual pathway glioma, IDs-related lymphoma, intraocular melanoma, islet cell tumor, Kaposi sarcoma, kidney cancer, Langerhans cell histiocytosis, laryngeal cancer, leukemia, lip and oral cavity cancer, male breast cancer, malignant fibrous histiocytoma, malignant germ cell tumor, malignant mesothelioma, medulloblastoma, melanoma, Merkel cell carcinoma, mesothelioma, oral cancer, multiple endocrine neoplasia syndrome, multiple myeloma, mycosis fungoides, myelodysplasia, myeloproliferative tumor, nasal and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin lymphoma, non-small cell lung cancer, oral cancer, oropharyngeal cancer, osteosarcoma, ovarian cancer, ovarian epithelial cancer, ovarian germ cell tumor, ovarian low malignant potential tumor, pancreatic cancer, pancreatic neuroendocrine tumor (islet cell tumor), papillomatosis, paraganglioma, paranasal sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pineal parenchymal tumor, pineoblastoma and supratentorial primitive neuroectodermal tumor, pituitary tumor, plasma cell tumor / multiple myeloma, pleuropulmonary blastoma, pregnancy and breast cancer, primary central nervous system lymphoma, primary liver cancer, primary metastatic cervical squamous cell carcinoma with occult, prostate cancer, rectal cancer, renal cell carcinoma, renal pelvis and ureter, respiratory tract cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, Sézary syndrome, skin cancer, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma (non-melanoma), stomach cancer, supratentorial primitive neuroectodermal tumor, T-cell lymphoma, testicular cancer,It can be used to treat pharyngeal cancer, thymoma and thymic cancer, thyroid cancer, transitional cell cancer, urethral cancer, uterine sarcoma, vaginal cancer, glioma of the visual pathway and hypothalamus, vulvar cancer, Waldenström macroglobulinemia, Wilms tumor, and one or more of systemic and central metastases of any of the foregoing.

[0138] The methods provided by the present disclosure include methods of treating cancer, where the cancer is selected from breast cancer and melanoma.

[0139] The methods provided by the present disclosure include methods of treating an inflammatory disease in a patient, comprising administering to the patient in need of treatment a therapeutically effective amount of a compound or pharmaceutical composition provided by the present disclosure.

[0140] Examples of inflammatory diseases include allergy, Alzheimer's disease, anemia, ankylosing spondylitis, arthritis, atherosclerosis, asthma, autism, arthritis, carpal tunnel syndrome, celiac disease, colitis, Crohn's disease, congestive heart failure, dermatitis, diabetes, diverticulitis, eczema, fibromyalgia, fibrosis, gallbladder disease, gastroesophageal reflux disease, Hashimoto's thyroiditis, heart attack, hepatitis, irritable bowel syndrome, kidney failure, lupus, multiple sclerosis, nephritis, neuropathy, pancreatitis, Parkinson's disease, psoriasis, polymyalgia, rheumatism, rheumatoid arthritis, sclerodermatitis, stroke, surgical complications, and ulcerative colitis.

[0141] The methods provided by the present disclosure include methods of treating an inflammatory disease in a patient, where the inflammatory disease is selected from, for example, acute respiratory distress syndrome, focal segmental glomerulonephritis, atherosclerosis / acute coronary syndrome, chronic obstructive pulmonary disease, asthma, inflammatory bowel disease, Crohn's disease, psoriasis, lupus, multiple sclerosis, inflammation in hypercholesterolemia, pain, diabetes, and rheumatoid arthritis.

[0142] The methods provided by the present disclosure include methods of treating an autoimmune disease in a patient, comprising administering to the patient in need of treatment a therapeutically effective amount of a compound or pharmaceutical composition provided by the present disclosure.

[0143] Compound (1) or a pharmaceutical composition thereof may be useful for treating autoimmune diseases. Autoimmune diseases can be defined as human diseases in which the immune system attacks its own proteins, cells, and / or tissues. An inclusive list and review of autoimmune diseases can be found, for example, in The Autoimmune Diseases, Rose and Mackay, 2014, Academic Press.

[0144] Examples of autoimmune diseases include Addison's disease, agammaglobulinemia, alopecia areata, amyloidosis, ankylosing spondylitis, anti-GBM / anti-TBM nephritis, antiphospholipid syndrome, autoimmune angioedema, autoimmune autonomic neuropathy, autoimmune encephalomyelitis, autoimmune hepatitis, autoimmune inner ear disease, autoimmune myocarditis, autoimmune pancreatitis, autoimmune retinopathy, autoimmune urticaria, axonal and neuronal neuropathy, barlow disease, Behcet's disease, benign mucous membrane pemphigoid, bullous pemphigoid, Castleman disease, celiac disease, Chagas disease, chronic inflammatory demyelinating polyneuropathy, chronic recurrent multifocal osteomyelitis, Churg-Strauss, cicatricial pemphigoid, Cogan syndrome, cold agglutinin disease, congenital heart block, coxsackie myocarditis, CREST syndrome, Crohn's disease, dermatitis herpetiformis, dermatomyositis, Devic's disease, discoid lupus, Dressler syndrome, endometriosis, eosinophilic esophagitis, eosinophilic fasciitis, erythema nodosum, essential mixed cryoglobulinemia, Evans syndrome, fibromyalgia, fibrosing alveolitis, giant cell arteritis, giant cell myocarditis, glomerulonephritis, Goodpasture syndrome, granulomatosis with polyangiitis, Graves' disease, Guillain-Barré syndrome, Hashimoto's thyroiditis, hemolytic anemia, Henoch-Schönlein purpura, herpes gestationis or pemphigoid gestationis, hypogammaglobulinemia, IgA nephropathy, IgG4-related sclerosing disease, immune thrombocytopenic purpura, inclusion body myositis, interstitial cystitis, juvenile arthritis, juvenile diabetes, juvenile myositis, Kawasaki disease, Lambert-Eaton syndrome, leukocytoclastic vasculitis, lichen planus, lichen sclerosus, ligneous conjunctivitis, linear IgA disease, lupus, Lyme disease, Ménière's disease, microscopic polyangiitis, mixed connective tissue disease, Mooren ulcer, Mucosa-Harbermann disease, multiple sclerosis, myasthenia gravis, myositis, narcolepsy, neuromyelitis optica, neutropenia, ocular cicatricial pemphigoid, optic neuritis, relapsing rheumatism, PANDAS, paraneoplastic cerebellar degeneration, paroxysmal nocturnal hemoglobinuria, Parry-Romberg syndrome, pars planitis, Parsonage-Turner syndrome, pemphigus, peripheral neuropathy, perivenous encephalomyelitis, pernicious anemia, POEMS syndrome, polyarteritis nodosa, polyglandular syndrome, polymyalgia rheumatica, polymyositis, postmyocardial infarction syndrome, postpericardiotomy syndrome, primary biliary cirrhosis, primary sclerosing cholangitis, progesterone dermatitis, psoriasis, psoriatic arthritis, pure red cell aplasia, pyoderma gangrenosum, Raynaud's phenomenon, reactive arthritis,Reflex sympathetic dystrophy, relapsing polychondritis, restless legs syndrome, retroperitoneal fibrosis, rheumatic fever, rheumatoid arthritis, sarcoidosis, Schmidt syndrome, scleritis, scleroderma, Sjogren's syndrome, sperm and testicular autoimmunity, stiff person syndrome, subacute bacterial endocarditis, Suzaku syndrome, sympathetic ophthalmia, Takayasu arteritis, temporal arteritis, thrombocytopenic purpura, Tolosa-Hunt syndrome, transverse myelitis, type 1 diabetes, ulcerative colitis, undifferentiated connective tissue disease, uveitis, vasculitis, vitiligo, and Wegener's granulomatosis are mentioned.

[0145] Compound (1) or its pharmaceutical composition can be used, for example, to treat autoimmune diseases such as lupus, graft-versus-host disease, hepatitis C-induced vasculitis, type I diabetes, multiple sclerosis, spontaneous abortion in pregnancy, atopic diseases, and inflammatory bowel diseases.

[0146] Compound (1) or its pharmaceutical composition can be administered together with one or more additional therapeutic agents for treating autoimmune diseases. Compound (1) or its pharmaceutical composition can be, for example, corticosteroids such as prednisone, budesonide, and prednisolone; Janus kinase inhibitors such as tofacitinib; calcineurin inhibitors such as cyclosporine and tacrolimus; mTOR inhibitors such as sirolimus and everolimus; IMDH inhibitors such as azathioprine, leflunomide, and mycophenolate; biological agents such as abatacept, adalimumab, anakinra, certolizumab, etanercept, golimumab, infliximab, ixekizumab, natalizumab, rituximab, secukinumab, tocilizumab, ustekinumab, and vedolizumab; and monoclonal antibodies such as basiliximab and daclizumab, and can be administered in combination with one or more immunosuppressive agents.

[0147] The method provided by the present disclosure includes a method of treating a disease in a patient, which includes administering a therapeutically effective amount of compound (1) to a patient in need of such treatment, and the disease is selected from acute coronary syndrome, acute lung injury, acute respiratory distress syndrome (ARDS), Alzheimer's disease, asthma, cardiovascular disease, chronic obstructive pulmonary disease (COPD), inflammatory bowel disease, major depressive disorder, multiple sclerosis, neuropathic pain, and rheumatoid arthritis. Compound (1) or a pharmaceutical composition thereof can be administered to a patient for treating viral diseases such as COVID-19 infection.

[0148] The method provided by the present disclosure includes a method of treating an inflammatory disease in a patient, which includes administering a therapeutically effective amount of compound (1) to a patient in need of treatment, and the disease is a respiratory disease.

[0149] The method provided by the present disclosure includes a method of treating a disease in a patient, which includes administering a therapeutically effective amount of the compound or pharmaceutical composition provided by the present disclosure to a patient in need of such treatment, and the disease is an age-related disease such as, for example, hearing loss, muscular dystrophy, Werner syndrome, cellular senescence, or Alzheimer's disease.

[0150] The method provided by the present disclosure includes a method of treating a disease in a patient, which includes administering a therapeutically effective amount of compound (1) or a pharmaceutical composition of such treatment to a patient in need of such treatment, and the disease is selected from sudden deafness, drug-induced deafness, age-related deafness, and Duchenne muscular dystrophy.

[0151] The amount of compound (1) or its pharmaceutical composition that would be effective in the treatment of cancer may depend, at least in part, on the nature of the disease and can be determined by standard clinical techniques known in the art. Additionally, in vitro or in vivo assays can be used to assist in identifying the optimal dosage range. The dosing regimen and dosing interval can also be determined by methods known to those of ordinary skill in the art. The amount of compound (1) administered may depend on, among other factors, the patient being treated, the patient's weight, the severity of the disease, the route of administration, and the judgment of the prescribing physician.

[0152] For systemic administration, the therapeutically effective dose can initially be estimated from in vitro assays. The initial dose can also be estimated from in vivo data, such as animal models, using techniques known in the art. Such information can be used to more accurately determine the useful dosage in humans. One of ordinary skill in the art may optimize the administration to humans based on the animal data.

[0153] The dosage of compound (1) and the appropriate dosing interval can be selected to maintain a continuously therapeutically effective concentration of compound (2) in the patient's blood, in certain embodiments, without exceeding the minimum harmful concentration.

[0154] The pharmaceutical composition containing compound (1) can be administered, for example, once every 4 days, once every 2 days, once a day, once a week, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 5 weeks, or once every 6 weeks. The dosing can be provided alone or in combination with other drugs and can be continued as long as necessary for effective treatment of the disease. The dosing can also be carried out using continuous or semi - continuous administration over a certain period. The dosing includes administering the pharmaceutical composition to a mammal, such as a human, in a fed or fasting state.

[0155] The pharmaceutical composition can be administered in a single dosage form or multiple dosage forms, or as continuous or cumulative dosages over a certain period. When multiple dosage forms are used, the amount of compound (1) contained within each of the multiple dosage forms can be the same or different.

[0156] A suitable daily dosage range for administration can be, for example, in the range of about 2 μg to about 200 mg of compound (1) per kilogram of body weight.

[0157] A suitable daily dosage range for administration can be, for example, in the range of about 1 μg to about 50 mg of compound (1) per square meter of body surface area (m 2 )).

[0158] Compound (1) can be administered to a patient for treating cancer, for example, in an amount of 0.001 mg / day to 100 mg / day, or at any other suitable daily dosage. The dosage can be, for example, 0.01 μg / kg body weight / week to 100 μg / kg body weight / week, or any other suitable dosage.

[0159] The pharmaceutical composition containing compound (1) can be administered to a patient for treating cancer so as to provide a therapeutically effective concentration of compound (2) in the patient's blood or plasma. The therapeutically effective concentration of compound (1) in the patient's blood can be, for example, 0.01 μg / L to 1,000 μg / L, 0.1 μg / L to 500 μg / L, 1 μg / L to 250 μg / L, or about 10 μg / L to about 100 μg / L. The therapeutically effective concentration of compound (2) in the patient's blood can be, for example, at least 0.01 μg / L, at least 0.1 μg / L, at least 1 μg / L, at least 10 μg / L, or at least 100 μg / L. The therapeutically effective concentration of compound (2) in the patient's blood can be, for example, less than an amount that causes unacceptable adverse effects including adverse effects on homeostasis. The therapeutically effective concentration of compound (2) in the patient's blood can be an amount sufficient to restore and / or maintain homeostasis in the patient.

[0160] The pharmaceutical composition provided by the present disclosure can be administered to a patient for treating a disease so as to provide a therapeutically effective concentration of compound (2) in the patient's blood over a period such as 4 hours, 8 hours, 12 hours, 16 hours, 20 hours, 1 day, or 2 days.

[0161] The amount of compound (1) administered can vary in the treatment regimen.

[0162] In addition to compound (1), the pharmaceutical composition provided by the present disclosure may further comprise one or more pharmaceutically active compounds. Such compounds may be provided, for example, to treat cancer being treated with compound (2), or to treat a disease, disorder, or condition other than cancer being treated with compound (2), to treat side effects caused by compound (2), to enhance the effectiveness of compound (2), and / or to modulate the activity of compound (2).

[0163] Compound (1) can be administered in combination with at least one other therapeutic agent. Compound (1) can be administered to a patient together with another compound for treating cancer in the patient. Compound (1) and at least one other therapeutic agent can act additively or, in certain embodiments, synergistically. The at least one additional therapeutic agent can be included in the same pharmaceutical composition or vehicle containing compound (1) or in a separate pharmaceutical composition or vehicle. Thus, the method provided by the present disclosure further comprises administering, in addition to compound (1), one or more therapeutic agents effective to treat cancer or a disease, disorder, or condition different from cancer. The method provided by the present disclosure comprises administering compound (1) and one or more other therapeutic agents, provided that the combination administration does not inhibit the therapeutic effectiveness of compound (2) and / or does not produce adverse combination effects.

[0164] The pharmaceutical composition containing compound (1) can be administered simultaneously with the administration of another therapeutic agent, which can be part of the same pharmaceutical composition as the pharmaceutical composition containing compound (1) or can be in a different pharmaceutical composition. Compound (1) can be administered before or after the administration of another therapeutic agent. In certain combination therapies, the combination therapy can include, for example, the alternating administration of compound (1) and a composition containing another therapeutic agent in order to minimize the harmful drug effects associated with a particular drug. When compound (1) is administered simultaneously with another therapeutic agent that can potentially cause harmful drug effects, such as including toxicity, the other therapeutic agent can be administered at a dose below the threshold at which a harmful drug reaction is induced.

[0165] The pharmaceutical composition containing compound (1) can be administered together with one or more substances, for example, to enhance, modulate, and / or control the release, bioavailability, therapeutic effectiveness, therapeutic efficacy, and / or stability of compound (1) and / or compound (2). For example, the pharmaceutical composition containing compound (1) can be co-administered with an active agent having a pharmacological effect that enhances the therapeutic effectiveness of compound (2).

[0166] Compound (1), or its pharmaceutical composition, can be administered in combination with an agent known or considered to be effective in treating diseases in a patient, such as cancer, autoimmune diseases, or inflammatory diseases, such as the same disease being treated with compound (1).

[0167] Compound (1), or its pharmaceutical composition, can be administered in combination with an agent known or considered to interfere with cell proliferation.

[0168] Compound (1), or its pharmaceutical composition, can be administered in combination with an agent known or considered to interfere with cell metabolism, an antimetabolite, interfere with RNA transcription, interfere with RNA translation, interfere with cellular protein synthesis, interfere with the synthesis of precursors for DNA synthesis and replication, interfere with purine synthesis, interfere with nucleoside synthesis, interact with mTOR, an mTOR inhibitor, interfere with cell cycle checkpoints.

[0169] Compound (1) or its pharmaceutical composition can be administered in combination with checkpoint inhibitors including CTLA-4 inhibitors such as ipilimumab, PD-1 inhibitors such as pembrolizumab and nivolumab, and / or PD-L1 inhibitors such as atezolizumab, avelumab, and durvalumab. Compound (1) or its pharmaceutical composition can be administered in combination with immunomodulators such as CD137 / 4-1BB, CD27, GIYR, and / or OC40.

[0170] Compound (1) or its pharmaceutical composition can be administered in combination with agents that are known or thought to be cytotoxic, cause DNA damage, cause cell cycle arrest, or cause mitotic cell death.

[0171] Compound (1) or its pharmaceutical composition can be administered in combination with agents that are known or thought to regulate glutathione concentration, regulate intracellular glutathione concentration, decrease intracellular glutathione concentration, reduce intracellular glutathione uptake, reduce glutathione synthesis, or reduce intracellular glutathione synthesis.

[0172] Compound (1) or its pharmaceutical composition can be administered in combination with agents that are known or thought to interfere with angiogenesis, reduce angiogenesis, or promote angiogenesis.

[0173] Compound (1) or its pharmaceutical composition can be administered in combination with agents that are known or thought to interfere with hormonal homeostasis, interfere with hormone synthesis, interfere with hormone receptor binding, or interfere with hormone signaling.

[0174] Compound (1) or its pharmaceutical composition can be administered in combination with a drug known or considered to interfere with growth factor homeostasis, interfere with growth factor receptor expression, interfere with growth factor binding to growth factor receptors, interfere with growth factor receptor signaling, interfere with Hedgehog (Hh) signaling, inhibit Hedgehog pathway signaling, inhibit ALK (anaplastic lymphoma kinase) pathway signaling, or inhibit the non-homologous end joining (NHEJ) pathway.

[0175] Compound (1) or its pharmaceutical composition is a VEGFR (vascular endothelial growth factor receptor) inhibitor, an RTK (receptor tyrosine kinase) inhibitor, a sodium channel current blocker, an aFAK (focal adhesion kinase) inhibitor, a GLI (glioma-related cancer gene) inhibitor, a GLI1 inhibitor, a GLI2 inhibitor, a GLI3 inhibitor, a MAPK (mitogen-activated protein kinase) inhibitor, a MAPK / ERK pathway (also known as the Ras-Raf-MEK-ERK pathway) inhibitor, a MEK1 inhibitor, a MEK2 inhibitor, a MEK5 inhibitor, a MEK5 / ERK5 inhibitor, an aRTA (tubular acidosis) inhibitor, an ALK (anaplastic lymphoma kinase) inhibitor, an Aa LK kinase inhibitor, a nuclear translocation inhibitor, a PORCN (hedgehog) inhibitor, a 5-ARI (5α-reductase inhibitor), a topoisomerase inhibitor, a Ras (rat sarcoma) inhibitor, a K-ras inhibitor, a CERK (ceramide kinase) inhibitor, a PKB (protein kinase B, also known as AKT) inhibitor, an AKT1 inhibitor, an EZH2 (enhancer of zeste homolog 2) inhibitor, a BET (bromodomain and extra-terminal domain motif) inhibitor, a SYK (spleen tyrosine kinase) inhibitor, a JAK (Janus kinase) inhibitor, a SYK / JAK inhibitor, an IDO (indoleamine-pyrrole 2,3-dioxygenase) inhibitor, an IDO1 inhibitor, an RXR (retinoid X receptor) activator, a selective RXR activator, a p-glycoprotein inhibitor, an ERK inhibitor, a PI3K (phosphatidylinositol-4,5'-bisphosphate 3-kinase inhibitor, BRD (bromodomain-containing protein) inhibitor, BRD2 inhibitor, BRD3 inhibitor, BRD4 inhibitor, BRDT (bromodomain testis-specific protein) inhibitor, reverse transcriptase inhibitor, NRT (nucleoside analog reverse transcriptase) inhibitor, PIM (Moloney virus proviral integration) inhibitor, EGFR (epidermal growth factor receptor) inhibitor, photosensitizer, radiation sensitizer, ROS (proto-oncogene, receptor tyrosine kinase) inhibitor, ROS1 (proto-oncogene 1) inhibitor, CK (casein kinase) inhibitor, CK2 inhibitor, Bcr-Abl (breakpoint cluster region-Abelson proto-oncogene) tyrosine kinase inhibitor, for example, dasatinib, microtubule stabilizer, microtubule depolymerization / disintegration inhibitor, DNA intercalator, androgen receptor antagonist, chemoprotectant, HDAC (histone deacetylase) inhibitor, DPP (dipeptidyl peptidase) inhibitor, DPP-4 inhibitor, BTK (Bruton's tyrosine kinase) inhibitor, kinase inhibitor, for example, imatinib, tyrosine kinase inhibitor, for example, nilotinib, ARP (poly(ADP-ribose) polymerase) inhibitor, CDK (cyclin-dependent kinase) inhibitor, CDK4 inhibitor, CDK6 inhibitor, CDK4 / 6 inhibitor, HIF1α (hypoxia-inducible factor 1-α) inhibitor, DNA ligase inhibitor, DNA ligase IV inhibitor, NHEJ (non-homologous end joining) inhibitor, DNA ligase IV, NHEJ inhibitor and RAF inhibitor, TKI and RAF inhibitor, TKI and RAF inhibitor, for example, sorafenib, PDT (photodynamic therapy) sensitizer, ATR (ataxia telangiectasia and Rad3-related protein kinase) inhibitor, or any combination of the foregoing, is known or contemplated and may be administered in combination with one or more agents.,

[0176] Compound (1) or its pharmaceutical composition is, for example, VEGFR inhibitors such as fruquintinib, motesanib / AMG-706, and batatinib; RTK inhibitors such as ponatinib; sodium channel blockers such as GS967; FAK inhibitors such as TAE226; GLI1 and GLI2 inhibitors such as GANT61; MEK inhibitors such as binimetinib; RTA inhibitors such as lenifanib; ALK inhibitors such as brigatinib; bromopyruvic acid; DNA alkylating agents such as thiotepa; nuclear translocation factors such as JSH-23; PORCn inhibitors such as Wnt-C59; 5α-reductase inhibitors such as dutasteride; topoisomerase inhibitors such as carvicine; RAS inhibitors such as Kobe0065; CerK inhibitors such as NVP-231; AKT inhibitors such as apocelitinib; EZH2 inhibitors such as GSK-503; BET bromodomain inhibitors such as OTX015; MEK5 / ERK5 inhibitors such as BIX02189; Syl / JAK inhibitors such as celedutatinib; IDO1 inhibitors such as NLG919; retinoid X receptor activators such as bexarotene; PGP inhibitors such as acotiamide or actotiamide HCl; Erk inhibitors such as SCH772984; PI3K inhibitors such as gedatolisib; JAK inhibitors such as ruxolitinib; AKT inhibitors such as afuresertib or afuresertib HCl; ALK1 inhibitors such as ceritinib; HDAC inhibitors such as abexinostat; DPP inhibitors such as oamarigliptin; EGFR inhibitors such as gefitinib; EZH2 inhibitors such as GSK126; BTK inhibitors such as ibrutinib; kinase inhibitors such as imatinine HCl; IDO inhibitors such as INCB024360; DNA cross-linking agents such as mitomycin C; tyrosine kinase inhibitors such as nilotinib; PARP inhibitors such as olaparib; tubulin stabilization promoters such as paclitaxel; CDK4 / 6 inhibitors such as palbociclib; RTK inhibitors such as sunitinib; PDT photosensitizers such as talaporfin; p-glycoprotein inhibitors such as tariquidar; ATR inhibitors such as VE-822; HDAC inhibitors such as PCI-24781; DPP inhibitors such as oamarigliptin; EGFR inhibitors such as gefitinib; EZH2 inhibitors such as GSK126; BTK inhibitors such as ibrutinib; IDO inhibitors such as INCB024360;It can be administered in combination with one or more chemotherapeutic agents, such as any of the foregoing combinations.

[0177] Compound (1) or its pharmaceutical composition can be administered in combination with another chemotherapeutic agent, such as N-acetylcysteine (NAC), doxorubicin, alemtuzumab, amifostine, arsenic trioxide, ascorbic acid, bendamustine, bevacizumab, bortezomib, busulfan, buthionine sulfoximine, carfilzomib, carmustine, clofarabine, cyclophosphamide, cyclosporine, cytarabine, dasatinib, dactinomycin, defibrotide, dexamethasone, docetaxel, doxorubicin, etoposide, filgrastim, floxuridine, fludarabine, gemcitabine, interferon alpha, ipilimumab, lenalidomide, leucovorin, melphalan, mycophenolate mofetil, paclitaxel, palifermin, panobinostat, pegfilgrastim, prednisolone, prednisone, revlimid, rituximab, sirolimus, sodium 2-mercaptoethanesulfonate (MESNA), sodium thiosulfate, tacrolimus, temozolomide, thalidomide, thioguanine, thiotepa, topotecan, velcade, or any of the foregoing combinations.

[0178] Compound (1) or its pharmaceutical composition can be used in combination therapy with other chemotherapeutic agents, including one or more antimetabolites such as folic acid analogs; pyrimidine analogs such as fluorouracil, floxuridine, and cytosine arabinoside; purine analogs such as mercaptopurine, thioguanine, and pentostatin; natural products such as vinblastine, vincristine, etoposide, teniposide, dactinomycin, daunorubicin, doxorubicin, bleomycin, mitomycin, mitomycin C, L-asparaginase, and interferon alpha; platinum coordination complexes such as cis-platinum and carboplatin; mitoxantrone; hydroxyurea; procarbazine; hormones and antagonists such as prednisone, hydroxyprogesterone caproate, medroxyprogesterone acetate, megestrol acetate, diethylstilbestrol, ethinyl estradiol, tamoxifen, testosterone propionate, fluoxymesterone, flutamide, and leuprolide; anti-angiogenic agents or inhibitors such as angiostatin, retinoic acid, paclitaxel, estradiol derivatives, and thiazolopyrimidine derivatives; apoptosis inhibitors; triptolide; colchicine; luliconazole; and radiotherapy.

[0179] Compound (1) or its pharmaceutical composition can be co-administered with a compound that inhibits DNA repair, such as, for example, O6-benzylguanine (O6-BG).

[0180] Compound (1) or its pharmaceutical composition is, for example, abarelix, abiraterone, abiraterone acetate, n-acetylcysteine, aclarubicin hydrochloride, adriamycin, adenine, afatinib, afatinib dimaleate, alemtuzumab, alendronate sodium, alitretinoin, allopurinol sodium, altretamine, amifostine, aminoglutethimide, aminolevulinic acid, amrubicin, amsacrine, anastrozole, angiostatin apremilast, aprepitant, arsenic trioxide, ascorbic acid, L-asparaginase, azacitidine, azathioprine sodium, bazedoxifene (serm), belinostat, bendamustine hcl, O6-benzylguanine, bevacizumab, bexarotene, bicalutamide, bilicodal, bleomycin sulfate, bortezomib, bosutinib, brequinar, buserelin, busulfan, buthionine sulfoximine, cabazitaxel, cabozantinib, capecitabine, carboplatin, carboquone, carfilzomib, carmofur, carmustine, ceritinib, chlorambucil, cisplatin, cladribine, clodronate disodium, clofarabine, crizotinib, cyclophosphamide, cyclosporine, cytarabine, cytosine arabinoside, dabrafenib, dacarbazine, dactinomycin, dasatinib, dactinomycin, daunorubicin, decitabine, debribotide, degarelix, degarelix acetate, dexamethasone, dexrazoxane hydrochloride, diazicon, diethylstilbestrol, docetaxel, doxifluridine, doxorubicin hydrochloride, doxorubicin free radical, drostanolone propionate, dutasteride, eltrombopag, enzalutamide, epirubicin hydrochloride, eribulin mesylate, erlotinib hydrochloride, estramustine phosphate sodium, ethinyl estradiol, topotecan phosphate, etoposide, everolimus, exemestane, fentanyl, filgrastim, fingolimod, floxuridine, fludarabine phosphate, fluorouracil, fluoxymesterone, flutamide, formestane, formyl melphalan, fosaprepitant, fotemustine, fulvestrant, gefitinib, gemcitabine hydrochloride, gemcitabine free base, glutathione, glyphosphoramide,Glyphosfin, Goserelin Acetate, Granisetron Hydrochloride, Heptaplatin, Hexyl 5-Aminolevulinate, Histrelin Acetate, Hydroxyprogesterone Caproate, Hydroxyurea, Sodium Ibandronate, Ibrutinib, Icotinib, Idarubicin HCl, Idelalisib, Idoxuridine, Ifosfamide, Interferon Alpha, Imatinib Mesylate, Imiquimod, Ingenol Mebutate, Ipilimumab, Irinotecan Hydrochloride, Ixabepilone, Lanreotide Acetate, Lapatinib Free Base, Lapatinib Ditosylate, Raloxifene, Lenalidomide, Letrozole, Leucovorin Calcium, Leuprolide Acetate, Levamisole Hydrochloride, Levoleucovorin Calcium, Iobenguane, Lobaplatin, Lomustine, Maropitant, Masoprocol, Mechlorethamine Hydrochloride, Megestrol Acetate, Medroxyprogesterone Acetate, Melphalan Hydrochloride, Mercaptopurine, Sodium Mercaptoethanesulfonate, Methotrexate, Methoxsalen, Methyl Aminolevulinate, Methylene Blue, Methyl Isoindigotin, Mifamurtide, Miltefosine, Milpratin, Mitamycin, Mitobronitol, Mitomycin C, Mitotane, Mitoxantrone Hydrochloride, Mycophenolate Mofetil, Naviximols, Nafarelin, Nandrolone, Nedaplatin, Nelarabine, Netupitant, Nilotinib, Nilutamide, Nimustine, Nintedanib, Nocodazole, Octreotide, Olaparib, Omacetaxine Mepesuccinate, Ondansetron Hydrochloride, Oxaliplatin, Paclitaxel, Palbociclib, Parifermin, Palonosetron Hydrochloride, Disodium Pamidronate, Panobinostat, Pasireotide, Pazopanib Hydrochloride, Pegfilgrastim, Pemetrexed Disodium, Pentostatin, Pepromycin, Pipobroman, Pirarubicin, Prexasoprol, Plicamycin, Pomalidomide, Porfimer Sodium, Porfiromycin, Pralatrexate, Prednimustine, Prednisolone, Prednisone, Procarbazine Hydrochloride, Quinagolide Hydrochloride, Raloxifene, Raltitrexed, Radotinib, Ranimustine, Retinoic Acid, Revlimid, Rituximab, Romidepsin, Luxitinib, Luxitinib Phosphate, Semustine, Sirolimus,Sodium thiosulfate, sorafenib free base, sorafenib tosylate, streptozocin, sufentanil, sunitinib, tacrolimus, talaporfin sodium, tamibarotene, tamoxifen, citrate, tapentadol, temoporfin, temozolomide, temsirolimus, teniposide, teriflunomide, tertiposide, testolactone, testosterone propionate, thalidomide, thioguanine, thiotepa, thimalfasin, toceranib phosphate, topotecan, hydrochloride, toremifene, toremifene citrate, trabectedin, trametinib, tretinoin, trilostane, triptorelin, tropisetron, uracil mustard, valrubicin, vandetanib, vedotin, vemurafenib, verteporfin, vinblastine, vincristine, vindesine, vinorelbine tartrate, vorinostat, and zoledronic acid, etc., can be administered in combination with one or more chemotherapeutic agents.

[0181] The compound of formula (1) or its pharmaceutical composition is, for example, abemaciclib, abiraterone acetate, ABVD, ABVE, ABVE-PC, AC, acalabrutinib, AC-T, ADE, ad-trastuzumab emtansine, afatinib, afatinib dimaleate, aldesleukin, alectinib, alemtuzumab, alpelisib, amifostine, aminolevulinic acid hydrochloride, anastrozole, apalutamide, aprepitant, arsenic trioxide, asparaginase Erwinia chrysanthemi, atezolizumab, avelumab, axicabtagene ciloleucel, axitinib, azacitidine, BEACOPP, belinostat, bendamustine hydrochloride, BEP, bevacizumab, bexarotene, bicalutamide, binimetinib, bleomycin sulfate, blinatumomab, bortezomib, bosutinib, brentuximab vedotin, brigatinib, BuMel, busulfan, cabazitaxel, cabozantinib S-malate, cabozantinib, CAF, carfilzomib, carmustine, carmustine implant, CEM, cemipimab-rwlc, ceritinib, cetuximab, CEV, chlorambucil, chlorambucil-prednisone, CHOP, cisplatin, cladribine, clofarabine, CMF, cobimetinib, copanlisib hydrochloride, COPDAC, COPP, COPP-ABV, crizotinib, CVP, cyclophosphamide, cytarabine, cytarabine liposome, dabrafenib mesylate, dacarbazine, dacomitinib, dactinomycin, daratumumab, darbepoetin alpha, dasatinib, daunorubicin hydrochloride, daunorubicin hydrochloride and cytarabine liposome, decitabine, denbufylline sodium, degarelix, denileukin diftitox, denosumab, dexamethasone, dexrazoxane hydrochloride, dinutuximab, docetaxel, doxorubicin hydrochloride, doxorubicin hydrochloride liposome, durvalumab, duvelisib, erlotinib, eltrombopag olamine, emapalumab-lzsg, enasidenib mesylate, encorafenib, enzalutamide, epirubicin hydrochloride, EPOCH, epoetin alpha, erdafitinib, eribulin mesylate,Erlotinib Hydrochloride, Etoposide, Etoposide Phosphate, Everolimus, Exemestane, FEC, Filgrastim, Fludarabine Phosphate, Fluorouracil Injection, Fluorouracil - Topical, Flutamide, Folfiri, Folfiri Bevacizumab, Folfiri Cetuximab, Folfox, Fostamatinib Disodium, FU-LV, Fulvestrant, Gefitinib, Gemcitabine Hydrochloride, Gemcitabine Cisplatin, Gemcitabine Oxaliplatin, Gemtuzumab Ozogamicin, Gilotrif Fumarate, Glasdegib Maleate, Glucarpidase, Goserelin Acetate, Granisetron, HPV Bivalent Vaccine, HPV Bivalent Vaccine, Recombinant HPV Monovalent Vaccine, HPV Monovalent Vaccine, Recombinant, HPV Quadrivalent Vaccine, HPV 9-Valent Recombinant Vaccine, Hydroxyurea, Hyper-CVAD, Ibritumomab Tiuxetan, Ibrutinib, ICE, Idarubicin Hydrochloride, Idelalisib, Ifosfamide, Imatinib Mesylate, Imiquimod, Inotuzumab Ozogamicin, Interferon α-2b Recombinant, Iobenguane, 131I、Ipilimumab, Irinotecan Hydrochloride, Irinotecan Hydrochloride Liposome, Ivosidenib, Ixabepilone, Ixazomib Citrate, JEB, Lanreotide Acetate, Lapatinib Ditosylate, Lartruvo Sulfate, Lenalidomide, Lenvatinib Mesylate, Letrozole, Leucovorin Calcium, Leuprolide Acetate, Lomustine, Lorlatinib, Lutetium Lu177-Dotatate, Mechlorethamine Hydrochloride, Megestrol Acetate, Melphalan, Melphalan Hydrochloride, Mercaptopurine, Mesna, Methotrexate, Methylnaltrexone Bromide, Midostaurin, Mitomycin C, Mitoxantrone Hydrochloride, Mogamulizumab-kpkc, Moxetumomab Pasudotox-tdfk, MVAC, Necitumumab, Nelarabine, Neratinib Maleate, Netupitant, Palonosetron Hydrochloride, Nilotinib, Nilutamide, Niraparib Tosylate Monohydrate, Nivolumab, Obinutuzumab, OEPA, Ofatumumab, OFF, Olaparib, Olalatumab, Omacetaxine Mepesuccinate, Ondansetron Hydrochloride, OPPA, Osimertinib Mesylate, Oxaliplatin, Paclitaxel, Paclitaxel Albumin-Stabilized Nanoparticle Formulation, PAD, Palbociclib, Parifermin, Palonosetron Hydrochloride, Palonosetron Hydrochloride and Netupitant, Pamidronate Disodium, Panitumumab, Panobinostat, Pazopanib Hydrochloride, PCV, PEB, Pegaspargase, Pegfilgrastim, Peginterferon Alpha-2b, Pembrolizumab, Pemetrexed Disodium, Pertuzumab, Prexasertib, Polatuzumab Vedotin-piiq, Pomalidomide, Ponatinib Hydrochloride, Pralatrexate, Prednisone, Procarbazine Hydrochloride, Propranolol Hydrochloride, Radium 223 Dichloride, Raloxifene Hydrochloride, Ramucirumab, Rasburicase, Rabipurumab-cwvz, R-CHOP, R-CVP, Recombinant HPV Bivalent Vaccine, Recombinant HPV Monovalent Vaccine, Recombinant HPV Quadrivalent Vaccine, Recombinant Interferon Alpha-2b, Regorafenib, R-EPOCH, Ribociclib, R-ICE, Rituximab, Rituximab, Hyaluronidase Human, Rolapitant Hydrochloride, Romidepsin, Romiplostim, Rubraca Acid, Rucaparib, Luxolitinib Phosphate, Cetuximab, Sipuleucel-t, Sonidegib, Sorafenib Tosylate,STANFORD V, sunitinib malate, TAC, tagraxofusp-erzs, talazoparib tosylate, talc, talimogene laherparepvec, tamoxifen citrate, temozolomide, temsirolimus, thalidomide, thioguanine, thiotepa, tisagenlecleucel, tocilizumab, topotecan hydrochloride, toremifene, TPF, trabectedin, trametinib, trastuzumab and hyaluronidase-oysk, trifluridine and tipiracil hydrochloride, triacetyluridine, VAC, valrubicin, VAMP, vandetanib, VeIP, vemurafenib, venetoclax, vinblastine sulfate, vincristine sulfate liposome, vinorelbine tartrate, vip, bimiralisib, vorinostat, XELIRI, XELOX, dip-Afibercept, zoledronic acid, or any combination of the foregoing, may be administered in combination with one or more chemotherapeutic agents such as.

[0182] The effectiveness of administering the compound (1) or its pharmaceutical composition for treating cancer, inflammatory diseases, or autoimmune diseases can be evaluated using in vitro and animal tests as well as in clinical trials.

[0183] The method of inhibiting p38α MAPK provided by the present disclosure includes contacting p38α MAPK with the compound provided by the present disclosure in a pocket near the ED substrate docking site of p38α MAPK.

[0184] The method of inhibiting p38α MAPK provided by the present disclosure does not result in the loss of p38α-dependent antagonistic responses. The p38α-dependent antagonistic responses relate to mitogen- and stress-activated protein kinase-I (MSKl) or MSK2. When targeting the pocket near the ED substrate docking site of p38α, the inhibitor provided by the present disclosure avoids interfering with CD-specific substrates including MSKl / 2, thus limiting inflammation through the expression of IL-10 and DUSP2.

[0185] Aspects of the Invention The present invention is further defined by the following aspects.

[0186] Aspect 1. Compound, crystalline 5-(dimethylamino)-N-(4-(morpholinomethyl)phenyl)naphthalene-1-sulfonamide dihydrochloride dihydrate:

Chemical formula

[0187] Aspect 2. The compound according to Aspect 1, wherein the compound is characterized by an XRPD pattern including diffraction peaks characteristic of at least 10.5° ± 0.2°, 13.9° ± 0.2°, 14.8° ± 0.2°, 17.2 ± 0.2°, 20.4 ± 0.2°, 22.6 ± 0.2°, 25.7 ± 0.2°, and 27.9 ± 0.2°, represented as 2θ angles and determined using Cu-Kα radiation.

[0188] Aspect 3. The compound according to Aspect 1, wherein the compound is characterized by an XRPD pattern including diffraction peaks characteristic of at least 10.5° ± 0.1°, 13.9° ± 0.1°, 14.8° ± 0.1°, 17.2 ± 0.1°, 20.4 ± 0.1°, 22.6 ± 0.1°, 25.7 ± 0.1°, and 27.9 ± 0.2°, represented as 2θ angles and determined using Cu-Kα radiation.

[0189] Aspect 4. The compound according to Aspect 1, wherein the compound is characterized by an XRPD pattern including diffraction peaks characteristic of at least 7.5 ± 0.2°, 8.5 ± 0.2°, 10.5° ± 0.2°, 12.8 ± 0.2°, 13.9° ± 0.2°, 14.8° ± 0.2°, 15.5 ± 0.2°, 17.2 ± 0.2°, 18.2 ± 0.2°, 20.1 ± 0.2°, 20.4 ± 0.2°, 21.1 ± 0.2°, 22.6 ± 0.2°, 22.9 ± 0.2°, 23.5 ± 0.2°, 23.8 ± 0.2°, 24.6 ± 0.2°, 25.7 ± 0.2°, 26.1 ± 0.2°, 26.4 ± 0.2°, 27.1 ± 0.2°, 27.5 ± 0.2°, 27.9 ± 0.2°, and 32.4 ± 0.2°, represented as 2θ angles and determined using Cu-Kα radiation.

[0190] Aspect 5. The compound is characterized by an XRPD pattern comprising diffraction peaks characteristic of at least 7.5±0.1°, 8.5±0.1°, 10.5°±0.1°, 12.8±0.1°, 13.9°±0.1°, 14.8°±0.1°, 15.5±0.1°, 17.2±0.1°, 18.2±0.1°, 20.1±0.1°, 20.4±0.1°, 21.1±0.1°, 22.6±0.1°, 22.9±0.1°, 23.5±0.1°, 23.8±0.1°, 24.6±0.1°, 25.7±0.1°, 26.1±0.1°, 26.4±0.1°, 27.1±0.1°, 27.5±0.1°, 27.9±0.1°, and 32.4±0.1°, represented as 2θ angles and determined using Cu-Kα radiation. The compound according to Aspect 1.

[0191] Aspect 6. The compound is characterized by an XRPD pattern substantially as shown in Figure 1. The compound according to any one of Aspects 1 to 5.

[0192] Aspect 7. The compound has a melting onset temperature of, for example, 161°C to 167°C, and the melting onset temperature is determined by differential scanning calorimetry. The compound according to any one of Aspects 1 to 6.

[0193] Aspect 8. The compound has a melting onset temperature of, for example, 164.3°C±0.5°C, and the melting onset temperature is determined by differential scanning calorimetry. The compound according to any one of Aspects 1 to 6.

[0194] Aspect 9. The compound has a melting enthalpy of, for example, 89 J / g to 99 J / g, and the melting enthalpy is determined by differential scanning calorimetry. The compound according to any one of Aspects 1 to 8.

[0195] Aspect 10. The compound has a melting enthalpy of, for example, 94.25 J / g±0.5 J / g, and the melting enthalpy is determined by differential scanning calorimetry. The compound according to any one of Aspects 1 to 8.

[0196] Aspect 11. The compound is, for example, a compound according to any one of Aspects 1 to 10, having a melting peak of 178.5 J / g to 184.5 J / g, the melting peak being determined by differential scanning calorimetry.

[0197] Aspect 12. The compound is, for example, a compound according to any one of Aspects 1 to 10, having a melting peak at 181.6 °C ± 2.0 °C, the melting peak being determined by differential scanning calorimetry.

[0198] Aspect 13. The compound is a compound according to any one of Aspects 1 to 12, substantially showing the differential scanning calorimetry curve shown in Figure 2.

[0199] Aspect 14. The compound is, for example, a compound according to any one of Aspects 1 to 13, having a weight loss of 13% to 15% at a temperature of 25 °C to 210 °C, the weight loss being determined by thermogravimetric analysis at a scanning rate of 2 °C / min.

[0200] Aspect 15. The compound is, for example, a compound according to any one of Aspects 1 to 13, having a weight loss of 13.9% ± 1.0% at a temperature of 25 °C to 210 °C, the weight loss being determined by thermogravimetric analysis at a scanning rate of 2 °C / min.

[0201] Aspect 16. The compound is a compound according to any one of Aspects 1 to 15, substantially showing the differential thermal measurement curve shown in Figure 3.

[0202] Aspect 17. The compound is, for example, a compound according to any one of Aspects 1 to 16, having a weight loss of 2% to 6% at a temperature of 25 °C to 122 °C, the weight loss being determined by thermogravimetric analysis at a scanning rate of 4.25 °C / min.

[0203] Aspect 18. The compound is, for example, a compound according to any one of Aspects 1 to 16, having a weight loss of 4.25% ± 1.0% at a temperature of 25 °C to 122 °C, the weight loss being determined by thermogravimetric analysis at a scanning rate of 4.25 °C / min.

[0204] Aspect 19. The compound according to any one of Aspects 1 to 16, wherein the compound substantially exhibits a differential thermal measurement curve shown in FIG. 4.

[0205] Aspect 20. A pharmaceutical composition comprising the compound according to any one of Aspects 1 to 19.

[0206] Aspect 21. The pharmaceutical composition according to any one of Aspects 1 to 19, wherein the pharmaceutical composition comprises a therapeutically effective amount of the compound for treating a disease in a patient.

[0207] Aspect 22. The pharmaceutical composition according to Aspect 21, wherein the disease is treated by inhibiting the p38α MAPK receptor.

[0208] Aspect 23. The pharmaceutical composition according to Aspect 21, wherein the disease is cancer.

[0209] Aspect 24. The pharmaceutical composition according to Aspect 21, wherein the disease is an inflammatory disease.

[0210] Aspect 25. The pharmaceutical composition according to Aspect 21, wherein the disease is an autoimmune disease.

[0211] Aspect 26. The pharmaceutical composition according to Aspect 21, wherein the disease is selected from acute lung injury, acute respiratory distress syndrome (ARDS), and chronic obstructive pulmonary disease (COPD).

[0212] Aspect 27. A method for treating a disease in a patient, comprising administering to a patient in need of such treatment a therapeutically effective amount of the compound according to any one of Aspects 1 to 19, wherein the disease is treated by inhibiting the p38α MAPK receptor.

[0213] Aspect 28. A method for treating a disease in a patient, comprising administering to a patient in need of such treatment a therapeutically effective amount of the compound according to any one of Aspects 1 to 19, wherein the disease is cancer.

[0214] Aspect 29. The method according to aspect 28, wherein the cancer is selected from breast cancer and melanoma.

[0215] Aspect 30. A method of treating a disease in a patient, comprising administering to a patient in need of such treatment a therapeutically effective amount of the compound according to any one of aspects 1 to 19, wherein the disease is an inflammatory disease.

[0216] Aspect 31. The method according to aspect 30, wherein the inflammatory disease is selected from acute respiratory distress syndrome, focal segmental glomerulonephritis, atherosclerosis / acute coronary syndrome, chronic obstructive pulmonary disease, asthma, inflammatory bowel disease, Crohn's disease, psoriasis, lupus, multiple sclerosis, inflammation in hypercholesterolemia, pain, diabetes, and rheumatoid arthritis.

[0217] Aspect 32. A method of treating a disease in a patient, comprising administering to a patient in need of such treatment a therapeutically effective amount of the compound according to any one of aspects 1 to 19, wherein the disease is an autoimmune disease.

[0218] Aspect 33. A method of treating a disease in a patient, comprising administering to a patient in need of such treatment a therapeutically effective amount of the compound according to any one of aspects 1 to 19, wherein the disease is an age-related disease.

[0219] Aspect 34. The method according to aspect 33, wherein the age-related disease is selected from hearing loss, muscular dystrophy, Werner syndrome, cellular senescence, and Alzheimer's disease.

[0220] Aspect 35. A method of treating a disease in a patient, comprising administering to a patient in need of such treatment a therapeutically effective amount of the compound according to any one of aspects 1 to 19, wherein the disease is selected from acute lung injury, acute respiratory distress syndrome (ARDS), and chronic obstructive pulmonary disease (COPD).

[0221] A method for inhibiting the p38α MAPK receptor, comprising contacting the p38α MAPK receptor with a compound according to any one of Aspects 1 to 19.

[0222] A method for inhibiting the p38α MAPK receptor in a patient, comprising administering to the patient a pharmacologically effective amount of a compound according to any one of Aspects 1 to 19.

[0223] The method according to Aspect 37, wherein inhibiting the p38α MAPK receptor comprises selectively inhibiting the p38α MAPK receptor.

[0224] The method according to Aspect 38, wherein inhibiting the p38α MAPK receptor does not result in loss of p38α - dependent antagonistic response.

[0225] The method according to Aspect 39, wherein the p38α - dependent antagonistic response relates to mitogen - activated and stress - activated protein kinase - 1 (MSK1) or MSK2.

[0226] The method according to any one of Aspects 37 to 40, wherein inhibiting the p38α MAPK receptor stabilizes endothelial or epithelial barrier function.

[0227] The method according to any one of Aspects 37 to 41, wherein inhibiting the p38α MAPK receptor reduces inflammation.

[0228] The method according to any one of Aspects 37 to 42, wherein inhibiting the p38α MAPK receptor reduces KPS - induced lung injury.

[0229] The method according to any one of Aspects 37 to 43, wherein inhibiting the p38α MAPK receptor regulates leukocyte trafficking.

[0230] A method according to any one of aspects 37 to 44, wherein inhibiting the p38α MAPK receptor regulates cytokine expression.

Example

[0231] The following examples will detail a method for preparing crystalline 5-(dimethylamino)-N-(4-(morpholinomethyl)phenyl)naphthalene-1-sulfonamide dihydrochloride dihydrate salt, the properties of this crystalline salt, and methods of using the crystalline salt provided by this disclosure. It will be apparent to those skilled in the art that many modifications to both materials and methods can be made without departing from the scope of this disclosure.

[0232] Example 1 Preparation of Compound (1) Compound (1) was prepared according to Scheme 5 disclosed in paragraph

[0277] of PCT International Publication No. PCT / US2019 / 064960.

[0233] 4-Nitrobenzyl chloride (1.0 equivalent) was added in isopropanol (5.0 volumes) under an inert atmosphere at 25°C to 30°C. The solution was stirred for 15 minutes, and 2.1 equivalents of morpholine were slowly added while maintaining the temperature at 25°C to 30°C. The mixture was heated to 65°C, and the progress of the reaction was monitored by TLC / HPLC. The reaction to provide 4-(4-nitrobenzyl)morpholine was complete after 3 hours.

[0234] 4-(4-Nitrobenzyl)morpholine in methanol was exposed to Raney Ni at 65°C to obtain 4-(morpholinomethyl)aniline.

[0235] 4-(Morpholinomethyl)aniline and 5-(dimethylamino)naphthalene-1-sulfonyl chloride were reacted with dansyl chloride in the presence of a tertiary amine base such as N-methylmorpholine in dichloromethane to obtain 5-(dimethylamino)-N-(4-(morpholinomethyl)phenyl)naphthalene-1-sulfonamide.

[0236] 5-(Dimethylamino)-N-(4-(morpholinomethyl)phenyl)naphthalene-1-sulfonamide was reacted with 4M HCl in 1,4-dioxane in methanol at a temperature of 0 °C to 25 °C to obtain 5-(dimethylamino)-N-(4-(morpholinomethyl)phenyl)naphthalene-1-sulfonamide dihydrochloride.

[0237] The dihydrochloride (1 equivalent) was suspended in methanol (3 volumes) and water (2 equivalents), and the suspension was stirred at 20 °C to 30 °C for 1 hour to obtain crystalline 5-(dimethylamino)-N-(4-(morpholinomethyl)phenyl)naphthalene-1-sulfonamide dihydrochloride dihydrate. The solid was filtered and washed with methanol (1.5 volumes).

[0238] X-ray powder diffraction (XRPD) was performed using a Shimadzu Lab XRD-6100 instrument with a Cu / K-α (λ = 1.5418 Å) source in continuous scan mode using a scintillation detector. The diffraction pattern was obtained over a scan range of 3° to 50° at a scan rate of 2 degrees per minute, a sampling pitch of 0.02 degrees, and a preset time of 0.6 seconds. Using this method, the XRPD patterns shown in Figures 1, 5, and 7 were obtained, and the crystal structures shown in Figures 9 - 10 were derived using the data.

[0239] Differential scanning calorimetry (DSC) was performed using a Perkin Elmer DSC4000 (version 13.2.1.0007) instrument in the temperature range of 30 °C to 300 °C, with a heating rate of 5 °C / min and a nitrogen flow rate of 80 mL / min, using a sample mass of 3 mg to 4 mg. Using this method, the DSC curves presented in Figures 4 and 6 were obtained.

[0240] Differential thermogravimetric analysis (TGA) was performed using a Shimadzu DTG-60 instrument with a sample mass of 10 mg over a temperature range of less than 25 °C to 400 °C at a heating rate of 2 °C / min. Using this method, the TGA curves presented in Figures 2 and 3 were obtained.

[0241] Finally, it should be noted that there are alternative ways to implement the embodiments disclosed in this specification. Accordingly, this embodiment is illustrative and not limiting, and the claims are not limited to the details given herein and may be modified within their scope and equivalents.

Claims

1. Compound, crystalline 5-(dimethylamino)-N-(4-(morpholinomethyl)phenyl)naphthalene-1-sulfonamide dihydrochloride dihydrate: 【Chemical Formula 1】

2. The compound according to claim 1, characterized by an XRPD pattern comprising diffraction peaks characteristic of at least 10.5°±0.2°, 13.9°±0.2°, 14.8°±0.2°, 17.2±0.2°, 20.4±0.2°, 22.6±0.2°, 25.7±0.2°, and 27.9±0.2°, represented as 2θ angles and determined using Cu-Kα radiation.

3. The compound according to claim 1, characterized by an XRPD pattern comprising diffraction peaks characteristic of at least 10.5°±0.1°, 13.9°±0.1°, 14.8°±0.1°, 17.2±0.1°, 20.4±0.1°, 22.6±0.1°, 25.7±0.1°, and 27.9±0.2°, represented as 2θ angles and determined using Cu-Kα radiation.

4. The compound according to claim 1, characterized by an XRPD pattern comprising diffraction peaks characteristic of at least 7.5±0.2°, 8.5±0.2°, 10.5°±0.2°, 12.8±0.2°, 13.9°±0.2°, 14.8°±0.2°, 15.5±0.2°, 17.2±0.2°, 18.2±0.2°, 20.1±0.2°, 20.4±0.2°, 21.1±0.2°, 22.6±0.2°, 22.9±0.2°, 23.5±0.2°, 23.8±0.2°, 24.6±0.2°, 25.7±0.2°, 26.1±0.2°, 26.4±0.2°, 27.1±0.2°, 27.5±0.2°, 27.9±0.2°, and 32.4±0.2°, represented as 2θ angles and determined using Cu-Kα radiation.

5. The compound according to claim 1, characterized by an XRD pattern comprising diffraction peaks characterized as at least 7.5±0.1°, 8.5±0.1°, 10.5°±0.1°, 12.8±0.1°, 13.9°±0.1°, 14.8°±0.1°, 15.5±0.1°, 17.2±0.1°, 18.2±0.1°, 20.1±0.1°, 20.4±0.1°, 21.1±0.1°, 22.6±0.1°, 22.9±0.1°, 23.5±0.1°, 23.8±0.1°, 24.6±0.1°, 25.7±0.1°, 26.1±0.1°, 26.4±0.1°, 27.1±0.1°, 27.5±0.1°, 27.9±0.1°, and 32.4±0.1°, represented as 2θ angles and determined using Cu-Kα radiation.

6. The compound according to any one of claims 1 to 5, characterized in that the compound has an XRD pattern substantially shown in FIG.

1.

7. The compound according to any one of claims 1 to 6, characterized in that the compound has a melting onset temperature of 161°C to 167°C, and the melting onset temperature is determined by differential scanning calorimetry.

8. The compound according to any one of claims 1 to 6, characterized in that the compound has a melting onset temperature of 164.3°C±0.5°C, and the melting onset temperature is determined by differential scanning calorimetry.

9. The compound according to any one of claims 1 to 8, characterized in that the compound has a melting enthalpy of 89 J / g to 99 J / g, and the melting enthalpy is determined by differential scanning calorimetry.

10. The compound according to any one of claims 1 to 8, characterized in that the compound has a melting enthalpy of 94.25 J / g±0.5 J / g, and the melting enthalpy is determined by differential scanning calorimetry.

11. The compound according to any one of claims 1 to 10, characterized in that the compound has a melting peak of 178.5 J / g to 184.5 J / g, and the melting peak is determined by differential scanning calorimetry.

12. The compound according to any one of claims 1 to 10, characterized in that the compound has a melting peak at 181.6°C±2.0°C, and the melting peak is determined by differential scanning calorimetry.

13. The compound according to any one of claims 1 to 12, characterized in that the compound substantially exhibits a differential scanning calorimetry curve shown in FIG.

2.

14. The compound according to any one of claims 1 to 13, wherein the compound has a weight loss of 13% to 15% at a temperature of 25°C to 210°C, and the weight loss is determined by thermogravimetric analysis at a scanning rate of 2°C / min.

15. The compound according to any one of claims 1 to 13, wherein the compound has a weight loss of 13.9% ± 1.0% at a temperature of 25°C to 210°C, and the weight loss is determined by thermogravimetric analysis at a scanning rate of 2°C / min.

16. The compound according to any one of claims 1 to 15, wherein the compound substantially exhibits a differential thermal measurement curve shown in FIG.

3.

17. The compound according to any one of claims 1 to 16, wherein the compound has a weight loss of 2% to 6% at a temperature of 25°C to 122°C, and the weight loss is determined by thermogravimetric analysis at a scanning rate of 4.25°C / min.

18. The compound according to any one of claims 1 to 16, wherein the compound has a weight loss of 4.25% ± 1.0% at a temperature of 25°C to 122°C, and the weight loss is determined by thermogravimetric analysis at a scanning rate of 4.25°C / min.

19. The compound according to any one of claims 1 to 16, wherein the compound substantially exhibits a differential thermal measurement curve shown in FIG.

4.

20. A pharmaceutical composition comprising the compound according to any one of claims 1 to 19.

21. The pharmaceutical composition according to any one of claims 1 to 19, wherein the pharmaceutical composition comprises a therapeutically effective amount of the compound for treating a disease in a patient.

22. The pharmaceutical composition according to claim 21, wherein the disease is treated by inhibiting the p38α MAPK receptor.

23. The pharmaceutical composition according to claim 21, wherein the disease is cancer.

24. The pharmaceutical composition according to claim 21, wherein the disease is an inflammatory disease.

25. The pharmaceutical composition according to claim 21, wherein the disease is an autoimmune disease.

26. The pharmaceutical composition according to claim 21, wherein the disease is selected from acute lung injury, acute respiratory distress syndrome (ARDS), and chronic obstructive pulmonary disease (COPD).

27. A method of treating a disease in a patient, comprising administering to a patient in need of such treatment a therapeutically effective amount of the compound according to any one of claims 1 to 19, wherein the disease is treated by inhibiting the p38α MAPK receptor.

28. A method for treating a disease in a patient, comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound according to any one of claims 1 to 19, wherein the disease is cancer.

29. The method according to claim 28, wherein the cancer is selected from breast cancer and melanoma.

30. A method for treating a disease in a patient, comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound according to any one of claims 1 to 19, wherein the disease is an inflammatory disease.

31. The method according to claim 30, wherein the inflammatory disease is selected from acute respiratory distress syndrome, focal segmental glomerulonephritis, atherosclerosis / acute coronary syndrome, chronic obstructive pulmonary disease, asthma, inflammatory bowel disease, Crohn's disease, psoriasis, lupus, multiple sclerosis, inflammation in hypercholesterolemia, pain, diabetes, and rheumatoid arthritis.

32. A method for treating a disease in a patient, comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound according to any one of claims 1 to 19, wherein the disease is an autoimmune disease.

33. A method for treating a disease in a patient, comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound according to any one of claims 1 to 19, wherein the disease is an age-related disease.

34. The method according to claim 33, wherein the age-related disease is selected from hearing loss, muscular dystrophy, Werner syndrome, cellular senescence, and Alzheimer's disease.

35. A method for treating a disease in a patient, comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound according to any one of claims 1 to 19, wherein the disease is selected from acute lung injury, acute respiratory distress syndrome (ARDS), and chronic obstructive pulmonary disease (COPD).

36. A method for inhibiting the p38α MAPK receptor, comprising contacting the p38α MAPK receptor with a compound according to any one of claims 1 to 19.

37. A method for inhibiting the p38α MAPK receptor in a patient, comprising administering to the patient a pharmacologically effective amount of a compound according to any one of claims 1 to 19.

38. The method according to claim 37, wherein inhibiting the p38α MAPK receptor comprises selectively inhibiting the p38α MAPK receptor.

39. The method according to claim 38, wherein inhibiting the p38α MAPK receptor does not result in loss of p38α-dependent antagonistic response.

40. The method according to claim 39, wherein the p38α-dependent antagonistic response relates to mitogen-activated and stress-activated protein kinase-1 (MSK1) or MSK2.

41. The method according to any one of claims 37 to 40, wherein inhibiting the p38α MAPK receptor stabilizes endothelial or epithelial barrier function.

42. The method according to any one of claims 37 to 41, wherein inhibiting the p38α MAPK receptor reduces inflammation.

43. The method according to any one of claims 37 to 42, wherein inhibiting the p38α MAPK receptor reduces KPS-induced lung injury.

44. The method according to any one of claims 37 to 43, wherein inhibiting the p38α MAPK receptor regulates leukocyte trafficking.

45. The method according to any one of claims 37 to 44, wherein inhibiting the p38α MAPK receptor regulates cytokine expression.

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